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Vaccination: Interrupting Spatial Disease Transmission 

Vaccination: Interrupting Spatial Disease Transmission
Chapter:
Vaccination: Interrupting Spatial Disease Transmission
Author(s):

Andrew Cliff

and Matthew Smallman-Raynor

DOI:
10.1093/med/9780199596614.003.0004
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date: 18 September 2020

  1. 4.1 Introduction [link]

  2. 4.2 History of Vaccination [link]

    • Early Vaccine Developments to 1900 [link]

    • Post-1900 Developments [link]

  3. 4.3 Vaccination Strategies and Disease Control [link]

    • Critical Community Size, Vaccination and Disease Elimination [link]

    • Vaccination Impact on Epidemic Cycles [link]

    • Ring Vaccination Strategies [link]

  4. 4.4 Global Programmes: The Expanded Programme on Immunization (EPI) [link]

    • EPI and the Global Immunization Vision and Strategy (GIVS) [link]

    • Trends in Global Vaccine Coverage [link]

    • Regional Contexts: WHO Western Pacific Region [link]

    • Beyond the EPI: Towards Second-Generation Programmes? [link]

  5. 4.5 National Programmes: Mass Vaccination and Disease Elimination in the United States [link]

    • Poliomyelitis [link]

    • Measles [link]

    • Economic Evaluations of Vaccination Programmes [link]

  6. 4.6 Vaccination Risks [link]

    • Faulty Vaccines [link]

    • False Alarms and Declining Herd Immunity [link]

    • Spatially Heterogeneous Vaccination Uptake [link]

  7. 4.7 Conclusion [link]

    • Appendix 4.1: Vaccine Developments [link]

4.1 Introduction

The impact of vaccination on the health of the world’s peoples is hard to exaggerate. With the exception of safe water, no other modality, not even antibiotics, has had such a major effect on mortality reduction and population growth.

Susan and Stanley Plotkin (2008, [link])

Vaccines are broadly defined by Parish (1968, [link]) as “preparations of any antigen which induces a specific active immunity to the corresponding infective agent”. The term ‘vaccine’ stems from the Latin word vacc(a) (cow) and was originally applied to the material used by Edward Jenner to infect humans with cowpox, the antibodies to which provided protection against smallpox. Vaccination – the process of conferring immunity to diseases through the administration of a vaccine – is now considered to be among the safest and most effective of health interventions, and has been used as a means of controlling an expanding list of infectious diseases since the late eighteenth century. In this chapter, we briefly review the history of vaccination (Section 4.2) and the principles that underpin the use of vaccination as a disease control strategy (Section 4.3). We then examine the vaccine control of common childhood and other infections at the global level through the World Health Organization’s Expanded Programme on Immunization (WHO-EPI) (Section 4.4) and at the national level through US strategies to eliminate the sustained indigenous transmission of poliomyelitis (Figure 4.1) and measles (Section 4.5). Finally, we look at the risks posed by faulty vaccines, vaccine scares and the spatially heterogeneous uptake of vaccines (Section 4.6). The chapter is concluded in Section 4.7.

Figure 4.1 Poster to encourage the uptake of oral poliovirus vaccine (OPV) in the United States, 1963. The “Wellbee” character was first used in US public health promotion campaigns to promote the uptake of Sabin Type-II poliovirus vaccine. It was later incorporated into campaigns for the promotion of diphtheria and tetanus immunisation, hand washing, physical fitness and injury prevention.

Figure 4.1
Poster to encourage the uptake of oral poliovirus vaccine (OPV) in the United States, 1963. The “Wellbee” character was first used in US public health promotion campaigns to promote the uptake of Sabin Type-II poliovirus vaccine. It was later incorporated into campaigns for the promotion of diphtheria and tetanus immunisation, hand washing, physical fitness and injury prevention.

Source: CDC/Mary Hilpertshauser (CDC Public Health Image Library ID #7224).

4.2 History of Vaccination

Historical summaries of vaccination are provided by Parish (1965, 1968) and Plotkin and Plotkin (2008). Practices analogous to the process of conferring increased resistance to infection (‘immunisation’) can be traced to antiquity. Parish (1968), for example, cites Mithridates VI of Pontus (134–63 bc) who, in an endeavour to protect himself against assassination by poisoning, experimented with sub-lethal doses of toxins to engender a tolerance to their effects. The first recorded evidence of the artificial induction of immunity to an infectious disease agent dates to the late sixth century ad and Chinese descriptions of the process of variolation in which immunity to smallpox was induced by exposure to smallpox pus or scabs derived from mild cases of the disease. The practice of variolation, which may have developed independently in India, spread westwards in later centuries, reaching North Africa by the thirteenth century and Europe by the eighteenth century. As early as 1714, a letter to the Philosophical Transactions of the Royal Society described inoculations conducted in Turkey, while Lady Mary Wortley Montagu, wife of the English Ambassador to Constantinople, introduced the practice to the British court in the same decade. By the 1720s, variolation had become accepted as a medical practice in Britain, if not so in some other European countries. Elsewhere, in North America, the Reverend Cotton Mather (1663–1728) learnt of the practice of variolation in West Africa from his slaves. Mather persuaded a medical colleague (Dr Zabdiel Boylston) to introduce the practice and 280 patients were inoculated with a fatality rate well below the 15 percent in the control population (Parish, 1968; Fenner, et al., 1988).

Early Vaccine Developments to 1900

The modern history of vaccines dates to the late eighteenth century and local knowledge from the southwest of England that dairy-farm workers who contracted cowpox were immune to smallpox. In 1774, Benjamin Jesty, a farmer in Dorset, drew on this knowledge to immunise experimentally his wife and sons against smallpox by exposing them to pustular material from a cow with cowpox. But it was the English physician, Edward Jenner (Figure 4.2), who studied and promoted the prophylactic powers of cowpox. On 14 May 1796, Jenner vaccinated James Phipps with material obtained from a pustule on the hand of a milkmaid. Six weeks later he attempted, without success, to infect Phipps with pus from a smallpox patient. After twelve more successful vaccinations, he privately published a report of his findings (Figure 4.3). Jenner’s ideas were triumphant. It was as if “…an angel’s trumpet had sounded over the earth” (Winslow, 1974; cited in Kiple, 1993, p. 1012). More than 100,000 were vaccinated in England in 1801 alone (cf. Figure 1.1). Within three years, Jenner’s Inquiry had been translated into six languages. Between 1804 and 1814, two million were vaccinated in Russia, and so on across the industrialising world.

Figure 4.2 Three pioneers in the development of human vaccines. (Left) Edward Jenner (1749–1823), a Gloucestershire physician and one of the discoverers of smallpox vaccination. In 1775 he began to examine the truth of the traditions that cowpox provided some protection against smallpox. In 1796 he confirmed his hypotheses by successfully inoculating an eight-year-old patient. Artist: John Raphael Smith (pastel, 423 mm × 332 mm). (Centre) Louis Pasteur (1822–95), a French chemist and the first scientist to attenuate viruses artificially for use in vaccines. He created several veterinary vaccines (including a vaccine for chicken cholera, the first vaccine to be developed in a laboratory) before successfully administering his human rabies vaccine in 1885. (Right) Maurice Hilleman (1919–2005), pictured c. 1958. Hilleman was an American microbiologist who worked on the development of over 40 vaccines in the post-war years, including mumps, measles, rubella, hepatitis A and hepatitis B.

Figure 4.2
Three pioneers in the development of human vaccines. (Left) Edward Jenner (1749–1823), a Gloucestershire physician and one of the discoverers of smallpox vaccination. In 1775 he began to examine the truth of the traditions that cowpox provided some protection against smallpox. In 1796 he confirmed his hypotheses by successfully inoculating an eight-year-old patient. Artist: John Raphael Smith (pastel, 423 mm × 332 mm). (Centre) Louis Pasteur (1822–95), a French chemist and the first scientist to attenuate viruses artificially for use in vaccines. He created several veterinary vaccines (including a vaccine for chicken cholera, the first vaccine to be developed in a laboratory) before successfully administering his human rabies vaccine in 1885. (Right) Maurice Hilleman (1919–2005), pictured c. 1958. Hilleman was an American microbiologist who worked on the development of over 40 vaccines in the post-war years, including mumps, measles, rubella, hepatitis A and hepatitis B.

Sources: (left) and (centre) Wellcome Library, London; (right) National Library of Medicine and the Walter Reed Army Medical Centre (Wikimedia Commons).

Figure 4.3 Jenner’s treatise on smallpox vaccination. In 1798 Edward Jenner proposed inoculation without contagion, using cowpox pustules instead of smallpox pustules as the source of inoculation material. Title page of Jenner’s self-published treatise on the subject from 1798 (left) and two subsequent publications offering further facts and observations from 1799 (centre) and 1800 (right).

Figure 4.3
Jenner’s treatise on smallpox vaccination. In 1798 Edward Jenner proposed inoculation without contagion, using cowpox pustules instead of smallpox pustules as the source of inoculation material. Title page of Jenner’s self-published treatise on the subject from 1798 (left) and two subsequent publications offering further facts and observations from 1799 (centre) and 1800 (right).

Jenner’s ideas were taken up enthusiastically in the New World by Dr Benjamin Waterhouse of Boston. In 1800 he vaccinated four of his children and placed them in the smallpox hospital, a highly contaminated environment. Their successful survival provided a boost for the practice, despite the offsetting of uncontrolled vaccination by charlatans and sharks. As the nineteenth century progressed, so standardisation of vaccination practice began to show very positive results. Its benign effect on death rates was everywhere evident and, in disciplined countries like England, Sweden and Prussia, smallpox deaths towards the end of the century were moving towards zero (Fenner, et al., 1988).

The Development of ‘Scientific Immunisation’

While the early work on smallpox vaccine was empirical and undertaken with no knowledge of the aetiology of the disease, the development of what Parish (1968, [link]) terms ‘scientific immunisation’ awaited advances on several fronts. Lancaster (1990) has tabulated the dates on which the ‘modern’ causes of 50 major diseases were established (see Table 4.1). Beginning with the identification of the intestinal worm Trichinella spiralis as the cause of trichniosis in 1835, the rate of detection of disease agents increased decade by decade from the 1830s until the 1880s when, in the golden age of bacteriology, the causes of nearly half the diseases listed were determined in a single decade. These advances, in turn, reflected the tools available for clinical examination and laboratory analysis. The compound microscope was not developed commercially until 1840; versions of the electron microscope to allow virus recognition did not appear until 1932, and entered general scientific use only from c. 1940. Examination of human tissues through the freezing, supporting and paraffin imbedding of samples was developed in 1843, 1853 and 1869 respectively. Stains for the study of cell structures began to be used from 1847.

Table 4.1 Discovery of the causes of 50 major human diseases, 1835–1935

Year

Disease

Modern name of organism

Discoverer

1835

Trichinosis

Trichinella spiralis

Paget, Owen

1843

Hookworm disease

Ancylostoma duodenale

Dubini

1849, 1876

Anthrax

Bacillus anthracis

Pollender, Koch

1853

Schistosomiasis

Schistosoma mansoni

Bilharz

1860, 1875

Amoebic dysentery

Entamoeba histolytica

Lambl, Loesch

1868

Leprosy

Mycobacterium leprae

Hansen

1868

Filariasis

Wuchereria bancrofti

Wucherer

1873

Relapsing fever

Treponema recurrentis

Obermeier

1877–78

Actinomycosis

Actinomyces israeli

Bollinger, Israel

1878–79, 1881

Suppuration

Staphylococcus aureus

Koch, Pasteur, Ogston

1879

Childbed fever

Streptococcus pyogenes

Pasteur

1879,1885

Gonorrhoea

Neisseria gonorrhoeae

Neisser, Bumm

1880

Malaria

Plasmodium falciparum

Laveran

1880,1884

Typhoid fever

Salmonella typhi

Eberth, Gaffky, Klebs, Koch

1881

Suppuration

Streptococcus pyogenes

Ogston

1881

Rabies

Rabies virus

Pasteur

1882

Glanders

Pseudomonas mallei

Loeffler & Schutz

1882

Tuberculosis

Mycobacterium tuberculosis

Koch

1882

Pneumonia

Klebsiella aerogenes

Friedländer

1883

Erysipelas

Streptococcus pyogenes

Fehleisen

1883

Cholera

Vibrio cholerae

Koch

1883–84

Diphtheria

Corynebacterium diphtheriae

Klebs, Loeffler

1884–89

Tetanus

Clostridium tetani

Nicolaeir, Kitasato

1886

Pneumonia

Streptococcus pneumoniae

Fraenkel

1886

Poliomyelitis

Poliovirus

Medin

1886, 1892

Smallpox

Smallpox virus

Buist, Guarnieri

1887

Cerebrospinal meningitis

Neisseria meningitidis

Weichselbaum

1887

Scarlet fever

Streptococcus pyogenes

Klein

1887

Undulant fever

Brucella melitensis

Bruce

1888

Food poisoning

Salmonella enteritidis

Gaertner

1889

Soft chancre

Haemophilus ducreyi

Ducrey

1892

Gas gangrene

Clostridium welchii

Welch

1894

Bubonic plague

Yersinia pestis

Kitasato, Yersin

1896

Botulism

Clostridium botulinum

Ermengem

1896

Bacillary dysentery

Shigella shigae

Shiga

1900

Paratyphoid fever

Salmonella paratyphi

Schottmüller

1901, 1903

Sleeping sickness

Trypanosoma gambiense

Forde, Bruce, Castellani

1903

Kala azar

Leishmania donovani

Leishman, Donovan

1905

Tick-borne relapsing fever

Borrelia duttoni

Dutton & Todd

1905

Syphilis

Treponema pallidum

Schaudinn & Hoffmann

1906

Whooping cough

Bordetella pertussis

Bordet & Gengou

1909

American trypanosomiasis

Trypanosoma cruzi

Chagas

1909

Bartonellosis

Bartonella bacilliformis

Barton

1911, 1938

Measles

Measles virus

Anderson & Goldberger, Plotz

1912

Tularemia

Francisella tularensis

McCoy & Chapin

1915

Leptospirosis

Leptospira icterohaemorrhagiae

Inada

1916

Typhus

Rickettsia prowazekii

Rocha Lima

1916

Rocky Mountain spotted fever

Rickettsia rickettsii

Ricketts

1917

Chickenpox

Varicella-zoster virus

Paschen

1933

Influenza

Influenza A virus

Smith, Andrewes & Laidlaw

Source: Cliff, et al. (1998, Table 1.5, [link][link]), modified from Lancaster (1990, Tables 2.3.1 and 2.3.2, [link], [link]).

Theory also played a critical role. Rokitansky’s great text on systematic pathology was published between 1842 and 1846, while Virchow announced the cell theory in 1855. By the middle of the century, a small number of diseases had been shown to be caused by living organisms (Table 4.1) and Henle had given his closely-reasoned account of the hypothesis that infectious diseases were not the result of unspecified ‘miasmas’ but transmitted by living organisms. The second half of the nineteenth century saw the heyday of bacteriological theory and practice with Louis Pasteur (1822–95), Ferdinand Cohn (1828–98) and Robert Koch (1843–1910) using the new laboratory tools to establish hypotheses of infection and contagion, often against entrenched opposition.

The early laboratory vaccines

The successful development of laboratory vaccines began with the pioneering work of the nineteenth-century French chemist, Louis Pasteur (Figure 4.2). Initially concerned with the development of attenuated veterinary vaccines for fowl cholera (1879), anthrax (1881) and, somewhat less successfully, swine erysipelas (1883), Pasteur’s rabies vaccine (1885) was the first laboratory vaccine to make an impact on human disease. Pasteur developed both the theory and the experimental practice for attenuating the (then unknown) rabies virus in the spinal chords of rabbits. Having initially demonstrated the protective effect of the vaccine on dogs, the first human test of the vaccine came in July 1885 when a nine-year-old boy who had been bitten by a rabid dog two days earlier was brought to Pasteur’s laboratory.

The successful development of vaccines against a series of major human bacterial diseases followed in short order. By 1896, the German scientist Wilhelm Kolle – an assistant to Robert Koch – had developed a heat-inactivated cholera vaccine that would serve as a model for cholera vaccines in the next century. In the same year, the British bacteriologist Almroth E. Wright developed a killed vaccine against typhoid fever that would subsequently be used by the British Army during the Second Boer War (1899–1902), while Waldemar Haffkine’s plague vaccine was developed and introduced in India in 1896–97 (Parish, 1968).

Post-1900 Developments

While antitoxins and vaccines were developed for a range of bacterial diseases (including anthrax, cholera, diphtheria, plague, tetanus, typhoid and tuberculosis) in the early decades of the twentieth century, the rapid development of virus vaccines awaited the advent of the electron microscope, from the 1930s, and methods for the laboratory culture of viruses. Vaccines for poliomyelitis and other common childhood diseases such as measles, mumps, and rubella followed in quick succession (Table 4.2). In the late twentieth and early twenty-first centuries, new methods and techniques have been adopted in vaccine development (notably recombinant DNA technology), while vaccine research has expanded to include cancers and non-infectious conditions such as addictions and allergies. To illustrate the pace and dimensions of these developments, Table 4.2 gives the year in which sample vaccines and antitoxins were licensed/approved in the USA from the implementation of the Biologics Control Act (1902) to the early twenty-first century, while Figure 4.4 gives a timeline for the introduction of sample vaccines in the United Kingdom.

Table 4.2 Year in which sample vaccines and antitoxins were licensed/approved in the USA, 1902–20101

Year

Disease

Vaccine

1914

Rabies

Rabies vaccine

1914

Typhoid fever

Typhoid vaccine

1915

Pertussis

Pertussis vaccine

1923

Diphtheria

Diphtheria toxoid

1935

Yellow fever

Live yellow fever vaccine (17D)

1937

Tetanus

Adsorbed form of tetanus toxoid

1945

Influenza

Inactivated influenza vaccine

1947

Diphtheria, tetanus

Combination diphtheria & tetanus toxoids

1949

Diphtheria, tetanus, pertussis

Diphtheria & tetanus toxoids & pertussis (DTP) vaccine

1952

Typhoid fever

Heat-phenol inactivated typhoid vaccine

1953

Yellow fever

Yellow fever vaccine

1953

Tetanus, diphtheria

Tetanus & diphtheria toxoids (adult formulation)

1955

Poliomyelitis

Inactivated poliovirus vaccine (IPV)

1961

Poliomyelitis

Oral polio vaccine (OPV) types 1 & 2

1962

Poliomyelitis

Oral polio vaccine (OPV) type 3

1963

Measles

Inactivated measles vaccine (Pfizer-vax Measles-K)

1963

Measles

Live virus measles vaccine (Rubeovax)

1963

Poliomyelitis

Trivalent oral polio vaccine (OPV)

1965

Measles

Live, further attenuated measles virus vaccine (Lirugen)

1967

Mumps

Mumps virus vaccine live (MumpsVax)

1968

Measles

Measles virus vaccine live (Attenuvax)

1969

Rubella

Rubella virus vaccines (Rubelogen; Meruvax; Cendevax)

1971

Measles, mumps, rubella

Combined measles, mumps & rubella (MMR) and measles & rubella (M-R-Vax) vaccines

1973

Measles, mumps

Measles & mumps virus vaccine live (M-M-Vax)

1974

Invasive meningococcal disease

Monovalent (group C) meningococcal polysaccharide vaccine

1977

Invasive pneumococcal disease

Pneumococcal vaccine

1978

Invasive meningococcal disease

Monovalent group A (Menomune-A), group C (Menomune-C) and bivalent groups A & C (Menomune-A/C) vaccines

1978

Yellow fever

Yellow fever vaccine (YF-Vax)

1979

Rubella

Rubella virus vaccine live (Meruvax)

1980

Rabies

Rabies vaccines (Imovax Rabies & Wyvac)

1981

Invasive meningococcal disease

Meningococcal polysaccharide vaccine, groups A, C, Y & W-135 Combined (Menomune A/C/Y/W-135)

1981

Hepatitis B

Hepatitis B viral vaccines

1983

Invasive pneumococcal disease

Enhanced pneumococcal polysaccharide vaccines (Pneumovax & Pnu-Imune)

1985

Invasive Hib disease

Haemophilus influenzae type b (Hib) polysaccharide vaccines (b-CAPSA 1, Hib-VAX & Hib-IMUNE)

1986

Hepatitis B

Hepatitis B vaccine (recombinant) (Recombivax)

1987

Invasive Hib disease

Protein-conjugated Haemophilus influenzae type b vaccine (ProHibit)

1988

Invasive Hib disease

Conjugated Haemophilus influenzae type b vaccine (HibTITER)

1989

Hepatitis B

Hepatitis B vaccine (recombinant) (Engerix-B)

1989

Typhoid fever

Typhoid vaccine live oral Ty21a (Vivotif)

1989

Invasive Hib disease

Haemophilus b conjugate vaccine (PedvaxHIB)

1990

Poliomyelitis

Poliovirus vaccine inactivated (Ipol)

1991

Diphtheria, tetanus, pertussis

Diphtheria & tetanus toxoids & acellular pertussis vaccine (Acel-Imune) for use as fourth & fifth doses

1992

Diphtheria, tetanus, pertussis

Diphtheria & tetanus toxoids & acellular pertussis vaccine adsorbed (Tripedia by Connaught) for use as fourth & fifth doses

1993

Invasive Hib disease, diphtheria, tetanus, pertussis

Combined Hib & whole cell DTP vaccine (Tetramune)

1993

Invasive Hib disease

Haemophilus b conjugate vaccines (ActHIB and OmniHib)

1994

Typhoid fever

Typhoid Vi polysaccharide vaccine (Typhim Vi)

1995

Varicella virus

Varicella virus vaccine live (Varivax)

1995

Hepatitis A

Hepatitis A vaccine, inactivated (Havrix)

1996

Hepatitis A

Hepatitis A vaccine, inactivated (Vaqta)

1996

Invasive Hib disese, Hepatitis B

Haemophilus b conjugate vaccine (meningococcal protein conjugate) & hepatitis B vaccine (recombinant) (Comvax)

1996

Diphtheria, tetanus, pertussis

Diphtheria & tetanus toxoids & acellular pertussis vaccine adsorbed (Tripedia by Aventis Pasteur)

1996

Diphtheria, tetanus, pertussis, invasive Hib disease

Combination diphtheria & tetanus toxoids & acellular pertussis & Hib vaccine (TriHIBit)

1996

Diphtheria, tetanus, pertussis

Diphtheria & tetanus toxoids & acellular pertussis vaccine (Acel-Imune)

1997

Diphtheria, tetanus, pertussis

Diphtheria & tetanus toxoids & acellular pertussis vaccine adsorbed (Infanrix)

1997

Rabies

Rabies vaccine (RabAvert)

1998

Diphtheria, tetanus, pertussis

Diphtheria & tetanus toxoids & acellular pertussis vaccine adsorbed (Certiva)

1998

Rotavirus gastroenteritis

Rotavirus vaccine, live, oral, tetravalent (RotaShield)

1998

Lyme disease

Lyme disease vaccine (recombinant) (LYMErix)

1999

Diphtheria, tetanus, pertussis

Diphtheria & tetanus toxoids & acellular pertussis vaccine adsorbed (Tripedia by Connaught)

2000

Invasive pneumococcal disease

Pneumococcal 7-valent conjugate vaccine (Prevnar)

2001

Hepatitis A, B

Hepatitis A inactivated & hepatitis B (recombinant) vaccine (Twinrix)

2002

Diphtheria, tetanus, pertussis

Diphtheria & tetanus toxoids & acellular pertussis vaccine adsorbed (Daptacel)

2002

Diphtheria, tetanus, pertussis, hepatitis B and poliomyelitis

Diphtheria & tetanus toxoids & acellular pertussis vaccine adsorbed, hepatitis B (recombinant) & inactivated poliovirus vaccine combined (Pediarix)

2003

Influenza A, B

Influenza vaccine, live, intranasal (FluMist)

2004

Tetanus, diphtheria

Tetanus & diphtheria toxoids adsorbed for adult use (Decavac)

2005

Invasive meningococcal disease

Meningococcal polysaccharide (serogroups A, C, Y & W-135) diphtheria toxoid conjugate vaccine (Menactra)

2005

Tetanus, diphtheria, pertussis

Tetanus toxoid, reduced diphtheria toxoid & acellular pertussis vaccines, adsorbed (Adacel, Boostrix)

2005

Influenza

Influenza virus vaccine, trivalent, types A & B (Fluarix)

2005

Measles, mumps, rubella, varicella virus

Measles, mumps, rubella & varicella virus vaccine live (Proquad)

2006

Rotavirus gastroenteritis

Rotavirus vaccine, live, oral, pentavalent (RotaTeq)

2006

Cervical cancer, genital warts

Human papillomavirus quadrivalent (Types 6, 11, 16, 18) vaccine, recombinant (Gardasil)

2007

Influenza A/H5N1

Influenza virus vaccine, H5N1

2007

Influenza A, B

Inactivated influenza virus vaccine (Afl uria)

2008

Rotavirus gastroenteritis

Rotavirus vaccine, live, oral (Rotarix)

2008

Diphtheria, tetanus, pertussis, poliomyelitis

DTaP-IPV vaccine (Kinrix)

2009

Infl uenza

Influenza A (H1N1) 2009 monovalent vaccines

2009

Cervical cancer

Human papillomavirus bivalent (Types 16, 18) vaccine, recombinant (Cervarix)

2009

Influenza A, B

Inactivated infl uenza virus vaccine, trivalent, types A & B (Fluzone High-Dose)

2010

Invasive pneumococcal disease

Pneumococcal 13-valent conjugate vaccine (Prevnar 13)

Notes:

1 The earliest licensed vaccines for sample diseases are shown in bold.

Source: data from the U.S. Food and Drug Administration (FDA).

Figure 4.4 Timeline of vaccine developments and the introduction of vaccines in the United Kingdom, 1796–2008. BCG (Bacillus Calmette-Guérin) tuberculosis vaccine. Hib (Haemophilus influenzae type b) vaccine. MMR (measles, mumps and rubella) combined vaccine. DTaP (diphtheria and tetanus toxoids, and acellular pertussis) vaccine. IPV (inactivated poliovirus vaccine). Td (tetanus and diphtheria toxoids) vaccine for adults. DTaP/IPV, DTaP/IPV/Hib and Td/IPV are combined preparations.

Figure 4.4
Timeline of vaccine developments and the introduction of vaccines in the United Kingdom, 1796–2008. BCG (Bacillus Calmette-Guérin) tuberculosis vaccine. Hib (Haemophilus influenzae type b) vaccine. MMR (measles, mumps and rubella) combined vaccine. DTaP (diphtheria and tetanus toxoids, and acellular pertussis) vaccine. IPV (inactivated poliovirus vaccine). Td (tetanus and diphtheria toxoids) vaccine for adults. DTaP/IPV, DTaP/IPV/Hib and Td/IPV are combined preparations.

Source: adapted from National Health Service (NHS) website.

In Appendix 4.1, we survey the development of vaccines against common infectious diseases that, today, form a central part of the routine childhood immunisation schedules of many countries and whose administration has been promoted since 1974 by the World Health Organization’s Expanded Programme on Immunization (WHO-EPI) (Section 4.4). These vaccines include those against diphtheria, tetanus, pertussis, poliomyelitis, measles, mumps and rubella, tuberculosis, Haemophilus influenzae type b, hepatitis B, invasive meningococcal and pneumococcal diseases and rotavirus gastroenteritis.

4.3 Vaccination Strategies and Disease Control

In Section 1.4, we saw how natural breaks in chains of infection for a specific disease can occur depending upon the sizes of the communities in which the disease agent is circulating. This gave rise to the notion of critical community size (CCS) – the population size of a community above which a sufficiently large stock of susceptibles will exist to enable the disease to be endemic – and below which the stock of susceptibles will not be large enough to maintain continuous chains of infection. In studies of the CCS, total population of a community is generally used as a convenient correlate of the difficult-to-estimate true susceptible population. Many studies have attempted to estimate the CCS for a range of common infectious diseases, and the results of these are summarised in Table 4.3, while Cliff, et al. (2000, [link][link]) have shown how the CCS is affected by factors such as geographical isolation and population density.

Table 4.3 Critical community size and disease properties: Icelandic evidence, 1888–1988

Critical community size (thousands)

Disease

Transmission

Immunity

Quoted1

Estimated CCS: Iceland

Normal infectious period in days (rank, 1 = shortest)

Scarlet fever

Intimate contact

Some repeat cases

48

15 (3)

Diphtheria

Normal contact

Usually lasting

67

21 (5)

Whooping cough

Airborne droplet

Lasting

106

18 (4)

Rubella

Airborne droplet

Lasting

132

151

7 (2=)

Measles

Airborne droplet

Lasting

250–500

259

7 (2=)

Influenza

Airborne droplet

Specific

1,000,000

102

5 (1)

Notes:

1 Ramsay and Emond (1978); Yorke, et al. (1979); Cliff, et al. (1986); and Cliff and Haggett (1990).

The basic notion of a threshold population below which an infectious disease becomes naturally self-extinguishing is paramount in articulating spatial control strategies. It implies that vaccination may be employed to reduce the susceptible population below some critical mass so that the chains of infection are broken. Once the susceptible population size of an area falls below the threshold then, when the disease concerned is eventually eliminated, it can only recur by reintroduction from other reservoir areas.

Critical Community Size, Vaccination and Disease Elimination

As shown in Table 4.3, the CCS for measles in an unvaccinated population is generally estimated to be around 250,000, above which the continuous epidemic chains displayed by settlement A in Figure 1.18C occur. In general, Griffiths (1973) has shown that the effect of vaccination is to raise the CCS for a given disease by a factor of 1/x2, where x is the proportion of the population that is not immunised by vaccination. Thus 50 percent immunisation against measles increases the critical community size from 250,000 to one million, while 90 percent immunisation increases the threshold to 25 million. So, for all practical purposes, when the percentage of the population vaccinated reaches the mid-90s, herd immunity is established and major epidemics will not occur; 100 percent vaccination is impossible to achieve because there always exist subgroups in a population who are inaccessible for any number of reasons (for example, objection to vaccination on religious grounds and inaccurate demographic recording). For a further consideration of the concept of CCS in relation to disease elimination, see Gay (2004).

Vaccination Impact on Epidemic Cycles

Although obviously not ideal, levels of vaccination well below herd immunity still severely disrupt chains of infection. Figure 4.5 shows the predicted effect of partial immunisation against measles, sustained over 15 years, at 80 percent of the one- to two-year-olds in a theoretical population. The slow damping of epidemic amplitude is evident as the cumulative impact of vaccination is felt. Eventually the endemic cycle is broken and whole epidemics are missed. Thus natural fadeout becomes very widespread, enhancing the possibility of local elimination and long-run global eradication of a disease.

Figure 4.5 Predicted effects of widespread measles immunisation. Application of the SIR model with the level of immunisation held constant for 15 years at 80 percent of one- to two-year-olds.

Figure 4.5
Predicted effects of widespread measles immunisation. Application of the SIR model with the level of immunisation held constant for 15 years at 80 percent of one- to two-year-olds.

Source: redrawn from Cliff, Smallman-Raynor, Haggett, et al. (2009, Figure 11.17, p. 654), adapted from Cutts (1990, Figure 10, [link]).

Ring Vaccination Strategies

The use of vaccination to establish a containing ‘ring of immunity’ around outbreaks has been considered by a number of workers; see, for example, Greenhalgh (1986) and Cliff and Haggett (1989). While the approach has occasionally been invoked for infectious diseases in human populations (Kretzschmar, et al., 2004; Lau, et al., 2005), the principles involved are readily illustrated by disease outbreaks among farm animals and we draw here on Tinline’s (1972) study of foot-and-mouth disease (FMD) in cattle.

Based on data relating to the 1967–68 epizootic of FMD in the United Kingdom, Tinline demonstrated that airborne spread of FMD virus downwind of an initially infected area was an important cause of additional disease outbreaks during the epizootic. To contain the disease, therefore, Tinline investigated the possibility of implementing vaccination in areas downwind of an initial outbreak in order to create a ‘buffer zone’ of immunity across which the virus could not easily pass. The principles involved are illustrated in Figure 4.6A. In the upper-left map of Figure 4.6A, the immediate (‘blanket’) vaccination of all herds downwind of the initial outbreak is called on confirmation of the outbreak. Recognising the manpower difficulties in the implementation of such a scheme, the remaining maps provide different schemes for the priority order (cell codes 1 and 2) of vaccine delivery. The results of simulations to test the efficacy of the different schemes are summarised in Figure 4.6B. With the exception of blanket vaccination, which would reduce the number of FMD cases to just 14 percent of the no vaccination scenario, Tinline identified ring vaccination scheme III as the most successful in reducing FMD transmission. The key feature of this scheme is the prioritisation of vaccination from the outside, in towards the initially infected area. Practical difficulties arise, however, in the implementation of such ring vaccination strategies, including the need for accurate 20-day wind forecasts from the date of the initial onset of the FMD outbreak; see Cliff and Haggett (1989) and Haggett (2000).

Figure 4.6 Ring vaccination schemes to control the spread of FMD virus. Tinline’s simulations of alternative vaccination schemes to control the spread of the 1967–68 epizootic of FMD among cattle herds in central England. (A) Prioritisation of vaccination of herds downwind of an initial outbreak (grey shaded) area. Each cell represents a 10 km × 10 km area, with priority of vaccination indicated by codes 1 (first priority) and 2 (second priority); code 0 = no vaccination. (B) Results of simulations of the number of FMD cases with distance from the initial outbreak area for no vaccination and blanket vaccination schemes (left) and for ring vaccination schemes I–III (right). Percentage estimates of the number of FMD cases in a given vaccination scenario, relative to the no vaccination scenario (= 100 percent), are given.

Figure 4.6
Ring vaccination schemes to control the spread of FMD virus. Tinline’s simulations of alternative vaccination schemes to control the spread of the 1967–68 epizootic of FMD among cattle herds in central England. (A) Prioritisation of vaccination of herds downwind of an initial outbreak (grey shaded) area. Each cell represents a 10 km × 10 km area, with priority of vaccination indicated by codes 1 (first priority) and 2 (second priority); code 0 = no vaccination. (B) Results of simulations of the number of FMD cases with distance from the initial outbreak area for no vaccination and blanket vaccination schemes (left) and for ring vaccination schemes I–III (right). Percentage estimates of the number of FMD cases in a given vaccination scenario, relative to the no vaccination scenario (= 100 percent), are given.

Source: redrawn from Haggett (2000, Figure 4.10, [link]), from Tinline (1972).

Applications: Equine Influenza in Eastern Australia

Perkins, et al. (2011) provide an example of the practical application of ring vaccination, in conjunction with blanket vaccination and predictive vaccination strategies, to contain an outbreak of equine influenza among horses in New South Wales and Queensland, Australia, in 2007 (Figure 4.7, located in the colour plate section). Ring vaccination of horses was implemented through the establishment of ‘vaccination buffer zones’ – strips or corridors of land that were typically ≥ 10 km wide and which were formed around infection foci with the view to limiting the lateral transmission of equine influenza by wind or other local spread mechanisms. Within the buffer zones, the objective was to vaccinate a sufficiently high proportion of horses to yield a barrier of immunity that would inhibit the spatial transmission of natural infection. The vaccination buffer zones in New South Wales were positioned sufficiently far away from areas of active infection to allow time for the development of immunity in vaccinated horses, and were formed in relation to natural geographical barriers, including lakes, escarpments and expanses of land in which horses were known to be absent. Within the buffer zones, vaccination was prioritised from the outside, in towards the infection foci (cf. Tinline’s ring vaccination schemes II and III in Figure 4.6). Queensland adopted a broadly similar approach, with an initial outer vaccination buffer zone, supplemented by an inner buffer zone when it became apparent that the rate of expansion of the disease in the area had begun to slow. Although the control of the outbreak was ultimately attributable to a range of control strategies that included movement controls and the implementation of biosecurity measures, available evidence suggests that equine influenza breached the vaccination buffer zones on only two occasions (Perkins, et al., 2011).

Figure 4.7. Ring vaccination to control the spread of equine influenza in New South Wales and Queensland, Australia, in 2007. The locations of infected premises are identified by the light and dark pink shading; beige-shaded zones, adjacent to the infected zones, had no reported cases. Vaccination buffer zones are represented by the diagonal shading.

Figure 4.7.
Ring vaccination to control the spread of equine influenza in New South Wales and Queensland, Australia, in 2007. The locations of infected premises are identified by the light and dark pink shading; beige-shaded zones, adjacent to the infected zones, had no reported cases. Vaccination buffer zones are represented by the diagonal shading.

Source: redrawn from Perkins, et al. (2011, Figure 1, [link]).

4.4 Global Programmes: The Expanded Programme on Immunization (EPI)

In Section 5.2, we examine one of the outstanding achievements of the World Health Organization (WHO): the global eradication of smallpox. Although the final eradication of smallpox was not formally announced by the WHO until December 1979, confidence was growing by the early 1970s that this would eventually be achieved. At this time, therefore, policy advisors both within and outside the WHO looked for an initiative which could become a successor to the smallpox eradication campaign. Representatives from industrialised countries, particularly those from Europe, were now seeing the results from their own immunisation programmes against a variety of childhood diseases and urged that these diseases be made the new WHO target area. The resolution creating the Expanded Programme on Immunization (EPI) was adopted by the World Health Assembly in 1974, with the initial aim of targeting six vaccine-preventable diseases (diphtheria, measles, pertussis, poliomyelitis, tetanus and tuberculosis) for a substantial reduction in global incidence. The term ‘expanded’ was used to recognise the fact that immunisation services of some sort already existed in virtually all countries. It indicated that the WHO programme would work to increase them, both in terms of coverage of the susceptible population and in terms of the number of antigens being used.

Programme policies of the EPI were formalised by the World Health Assembly in 1977. It was at this time that the twin goals were set of: (i) providing immunisation services for all children of the world by 1990 and (ii) giving priority to developing countries. In the formal terms of the policy documents, the EPI is “a world-wide collaborative programme of Member States in the sense that it aims at total coverage of susceptible populations and age-groups throughout the world, irrespective of whether or not WHO is directly involved” (Keja and Henderson, 1984, [link]).

When the EPI began, no global immunisation information system existed and best guesses were that vaccine coverage for the six EPI target diseases was < 10 percent in developing countries (excluding China). In light of knowledge subsequently obtained, it seems likely that the figure was actually < 5 percent. From this low baseline, immunisation services in developing countries were extended to almost 80 percent of children (aged < 1 year) by the mid-1990s (Bland and Clements, 1998). Nevertheless, some 34 million children were being born each year in areas of the world that lacked adequate immunisation programmes. In response, the Global Alliance for Vaccines and Immunization (GAVI) was established in 2000 with the specific aim of promoting the reach of the EPI in the world’s poorest countries. The GAVI Alliance is formed as a coalition of UN agencies and institutions (WHO, UNICEF and the World Bank), the Bill and Melinda Gates Foundation, the Rockefeller Foundation, the vaccine industry, NGOs, and donor and implementing countries, among others. National governments of 72 countries with a gross national income (GNI) per capita of < US$1,000 in 2003 are eligible to apply for support from the GAVI Alliance for the supply of vaccines and the strengthening of health systems and immunisation services.

EPI and the Global Immunization Vision and Strategy (GIVS)

The operations of the EPI are currently set within the framework of the Global Immunization Vision and Strategy (GIVS). GIVS was launched as a collaborative initiative of the WHO and UNICEF in 2006 with the aim of providing a 10-year framework for controlling morbidity and mortality from vaccine-preventable diseases. As described in the GIVS framework document (World Health Organization, 2005a), the strategic areas of GIVS include: (i) the immunisation of more people against more diseases; (ii) the introduction of new vaccines and technologies; (iii) the integration of other critical health interventions with immunisation; and (iv) the management of vaccination programmes within the context of global interdependence. The specific goals of GIVS are summarised in Table 4.4. Set relative to the year 2000, these goals include a two-thirds (or greater) reduction in childhood morbidity and mortality due to vaccine-preventable diseases by 2015 – a contribution to achieving the United Nations’ Millennium Development Goal 4 (‘to reduce childhood mortality’).

Table 4.4 Key goals of the WHO-UNICEF Global Immunization Vision and Strategy (GIVS)

By 2010 or earlier

Increase coverage. Countries will reach at least 90% national vaccination coverage and at least 80% vaccination coverage in every district or equivalent administrative unit.

Reduce measles mortality. Globally, mortality due to measles will have been reduced by 90% compared to the 2000 level.

By 2015 or earlier

Sustain coverage. The vaccination coverage goal reached in 2010 will have been sustained.

Reduce morbidity and mortality. Global childhood morbidity and mortality due to vaccine-preventable diseases will have been reduced by at least two-thirds compared to 2000 levels.

Ensure access to vaccines of assured quality. Every person eligible for immunisation included in national programmes will have been offered vaccination with vaccines of assured quality according to established national schedules.

Introduce new vaccines. Immunisation with newly-introduced vaccines will have been offered to the entire eligible population within five years of the introduction of these new vaccines in national programmes.

Ensure capacity for surveillance and monitoring. All countries will have developed the capacity at all levels to conduct case-based surveillance of vaccine-preventable diseases, supported by laboratory confirmation where necessary, in order to measure vaccine coverage accurately and use these data appropriately.

Strengthen systems. All national immunisation plans will have been formulated as an integral component of sector-wide plans for human resources, financing and logistics.

Assure sustainability. All national immunisation plans will have been formulated, costed and implemented so as to ensure that human resources, funding and supplies are adequate.

Source: World Health Organization (www.who.int).

Additional EPI Target Diseases

Within the framework of GIVS, the EPI has been charged with continuing to promote the introduction of appropriate new vaccines into national immunisation programmes. The original six EPI target diseases were selected in 1974 on the basis of their high incidence in countries around the world and the availability of safe, effective and affordable vaccines. As new vaccines have been developed, so additional diseases have been added to the EPI list. Many countries have included H. influenzae type b (Hib) and hepatitis B vaccines in their routine infant immunisation schedules. A number of countries are also in the process of including pneumococcal conjugate vaccine, rotavirus vaccine and human papillomavirus vaccine, while yellow fever vaccine has been included in some at-risk countries.

Trends in Global Vaccine Coverage

Regional overviews of immunisation practices in the twenty-first century are provided in Plotkin, et al. (2008, pp. 1479–1571). Figure 4.8 plots, as line traces, WHO/UNICEF estimates (broken line traces) and officially reported levels (full line traces) of annual global vaccine coverage for the six original EPI target diseases (graphs A–G) and three additional target diseases (graphs H–J) in the 30 years to 2009. The discrepancies between the two sets of coverage data arise from situations in which the official reports, supplied by WHO member states, are deemed by the WHO/UNICEF to be compromised and therefore potentially misleading (Burton, et al., 2009; World Health Organization, 2010a). Global counts of the target diseases are plotted, where available, as the bar charts.

Figure 4.8 Trends in global vaccine coverage, 1980–2009. Official reports by WHO member states (full line traces) and WHO/UNICEF estimates (broken line traces) of annual global vaccine coverage for the original six EPI target diseases (graphs A–G) and for three additional target diseases (H–J). Vaccine coverage is expressed as a percentage of the target population for vaccination, most commonly formed as the number of infants surviving the first year of life. Bar charts plot the global count of reported cases of sample diseases. (A) Diphtheria, coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3) at < 1 year of age. (B) Measles, coverage with the first dose of measles-containing vaccine (MCV) at < 1 year of age. (C) Pertussis, coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3) at < 1 year of age. (D) Poliomyelitis, coverage with the third dose of oral or inactivated poliovirus vaccine (Pol3) at < 1 year of age. (E) Tetanus (neonatal), coverage with at least two doses of tetanus toxoid (TT2+) among pregnant women in priority countries for neonatal tetanus elimination and developing countries where tetanus is in the national immunisation schedule for women of childbearing-age. (F) Tetanus (total), coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3) at < 1 year of age. (G) Tuberculosis, coverage with BCG vaccine at < 1 year of age. (H) H. influenzae type b, coverage with the third dose of H. influenzae type b vaccine (Hib3) at < 1 year of age. (I) Hepatitis B, coverage with the third dose of hepatitis B vaccine (HepB) at < 1 year of age. (J) Yellow fever, coverage with yellow fever vaccine (YFV) at < 1 year of age in countries that are considered to be at risk for the disease.

Figure 4.8
Trends in global vaccine coverage, 1980–2009. Official reports by WHO member states (full line traces) and WHO/UNICEF estimates (broken line traces) of annual global vaccine coverage for the original six EPI target diseases (graphs A–G) and for three additional target diseases (H–J). Vaccine coverage is expressed as a percentage of the target population for vaccination, most commonly formed as the number of infants surviving the first year of life. Bar charts plot the global count of reported cases of sample diseases. (A) Diphtheria, coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3) at < 1 year of age. (B) Measles, coverage with the first dose of measles-containing vaccine (MCV) at < 1 year of age. (C) Pertussis, coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3) at < 1 year of age. (D) Poliomyelitis, coverage with the third dose of oral or inactivated poliovirus vaccine (Pol3) at < 1 year of age. (E) Tetanus (neonatal), coverage with at least two doses of tetanus toxoid (TT2+) among pregnant women in priority countries for neonatal tetanus elimination and developing countries where tetanus is in the national immunisation schedule for women of childbearing-age. (F) Tetanus (total), coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3) at < 1 year of age. (G) Tuberculosis, coverage with BCG vaccine at < 1 year of age. (H) H. influenzae type b, coverage with the third dose of H. influenzae type b vaccine (Hib3) at < 1 year of age. (I) Hepatitis B, coverage with the third dose of hepatitis B vaccine (HepB) at < 1 year of age. (J) Yellow fever, coverage with yellow fever vaccine (YFV) at < 1 year of age in countries that are considered to be at risk for the disease.

Source: redrawn from World Health Organization (2010a, [link], [link], [link], [link], [link], [link], [link], [link], [link], [link]).

The Original EPI Target Diseases

A prominent feature of Figures 4.8A–G is the rapid increase during the 1980s in global vaccine coverage for the six original EPI target diseases. This development was driven by the push to achieve the WHO/UNICEF goals for Universal Childhood Immunization, with the specific aim of immunising 80 percent of all children by 1990 (Figure 4.9). The increase in global vaccine coverage at this time was attributable to both an increase in the number of WHO member states that had established immunisation services and to an increase in vaccine coverage in these member states, most notably in the WHO Regions of Africa, Eastern Mediterranean, South-East Asia and the Western Pacific. Thereafter, global vaccine coverage for the target diseases grew steadily, with WHO/UNICEF estimates ranging between 75 and 88 percent in 2009. Some impression of the associated reduction in disease activity is provided by the bar charts, and by Table 4.5 which gives the global incidence of the EPI target diseases in 1980 and 2009. Over the 30-year interval, reported measles cases fell from > 4.21 million (1980) to < 0.23 million (2009), diphtheria from little under 100,000 cases (1980) to < 1,000 cases (2009), while pertussis fell from > 1.98 million cases to < 0.11 million cases (World Health Organization, 2010a).

Figure 4.9 The Expanded Program on Immunization in the Americas. The ‘Make Measles History’ campaign was launched when the Caucus of Caribbean Community and Common Market (CARICOM) Ministers Responsible for Health resolved, in 1988, to eliminate the indigenous transmission of measles in the Caribbean by 1995. A primary strategy of the campaign was to immunise simultaneously all susceptible people in the region and, to these ends, May 1991 was declared ‘Measles Elimination Month’. In this month, an attempt was made to immunise all people aged < 15 years against measles, regardless of vaccination status or measles history.

Figure 4.9
The Expanded Program on Immunization in the Americas. The ‘Make Measles History’ campaign was launched when the Caucus of Caribbean Community and Common Market (CARICOM) Ministers Responsible for Health resolved, in 1988, to eliminate the indigenous transmission of measles in the Caribbean by 1995. A primary strategy of the campaign was to immunise simultaneously all susceptible people in the region and, to these ends, May 1991 was declared ‘Measles Elimination Month’. In this month, an attempt was made to immunise all people aged < 15 years against measles, regardless of vaccination status or measles history.

Source: Castillo-Solórzano, et al. (2009, unnumbered plate, [link]).

Table 4.5 Reported global incidence of WHO EPI target diseases, 1980 and 2009

Global incidence

Disease

1980

2009

Original EPI target diseases

Diphtheria

97,511

857

Measles

4,211,431

222,408

Pertussis

1,982,355

106,207

Poliomyelitis

52,795

1,779

Tetanus

neonatal

13,005

4,712

total

114,251

9,836

Tuberculosis

Additional EPI target diseases

H. influenzae type b

Hepatitis B

Yellow fever

144

1,044

Source: data from World Health Organization (2010a).

Additional EPI Target Diseases

An increasing proportion of WHO member states have incorporated Hib (Figure 4.8H) and hepatitis B (Figure 4.8I) vaccines into routine immunisation services since the 1990s, with WHO/UNICEF estimates of global vaccine coverage rising to 38 percent (Hib) and 70 percent (hepatitis B) of the respective target populations by 2009. Of the 45 member states and territories of the WHO Africa (31), Americas (12) and Eastern Mediterranean (2) Regions that are deemed to be at risk for yellow fever, 35 had incorporated yellow fever into their routine immunisation schedules by 2009 and vaccine coverage approximated 50 percent (Figure 4.8J). Additional vaccines had also been incorporated into the routine immunisation schedules of WHO member states by 2009, including pneumococcal conjugate (44 member states), rotavirus (22), rubella (130) and human papillomavirus (29) vaccines (World Health Organization, 2010a).

Regional Contexts: WHO Western Pacific Region

As Figure 2.31 shows, the WHO Western Pacific Region (WPR) encompasses a vast swathe of continental east Asia and the western Pacific Ocean. In 2010, the combined population of the region’s 27 member states was 1,776 million, with China (1,336 million), Japan (128 million), Philippines (88 million) and Vietnam (87 million) as the most populous states and the remote south Pacific islands of Tuvalu (11,000), Nauru (10,000), and Niue (2,000) as the least populous.

In the 1970s and 1980s, the establishment of routine immunisation systems for the EPI target diseases formed the main focus of EPI activities in the region (Figure 4.10). With the 1988 resolution of the World Health Assembly to eradicate poliomyelitis globally (Section 5.3), the WPR-EPI entered a new phase that centred on disease eradication, elimination and accelerated control. Sustained interruption of wild poliovirus transmission was achieved within 10 years (Figure 4.10D); the last indigenous cases of the disease were recorded in 1997 and the Western Pacific Region was certified to be poliomyelitis-free on 29 October 2000 (Figure 4.11).

Figure 4.10 Trends in vaccine coverage in the WHO Western Pacific Region, 1980–2010. WHO/UNICEF estimates of annual vaccine coverage for the original six EPI target diseases (graphs A–F) and for two additional target diseases (G, H) for individual member states (fine line traces) and for the Western Pacific Region as a whole (heavy line trace). Vaccine coverage is expressed as a percentage of the target population for vaccination. Bar charts plot the regional count of reported cases for sample diseases. (A) Diphtheria, coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3). (B) Measles, coverage with the first dose of measles-containing vaccine (MCV). (C) Pertussis, coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3). (D) Poliomyelitis, coverage with the third dose of oral or inactivated poliovirus vaccine (Pol3). (E) Tetanus (total), coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3). (F) Tuberculosis, coverage with Bacille Calmette-Guérin (BCG) vaccine. (G) H. influenzae type b, coverage with the third dose of H. influenzae type b vaccine (Hib3). (H) Hepatitis B, coverage with the third dose of hepatitis B vaccine (HepB).

Figure 4.10
Trends in vaccine coverage in the WHO Western Pacific Region, 1980–2010. WHO/UNICEF estimates of annual vaccine coverage for the original six EPI target diseases (graphs A–F) and for two additional target diseases (G, H) for individual member states (fine line traces) and for the Western Pacific Region as a whole (heavy line trace). Vaccine coverage is expressed as a percentage of the target population for vaccination. Bar charts plot the regional count of reported cases for sample diseases. (A) Diphtheria, coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3). (B) Measles, coverage with the first dose of measles-containing vaccine (MCV). (C) Pertussis, coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3). (D) Poliomyelitis, coverage with the third dose of oral or inactivated poliovirus vaccine (Pol3). (E) Tetanus (total), coverage with the third dose of diphtheria, tetanus and pertussis vaccine (DTP3). (F) Tuberculosis, coverage with Bacille Calmette-Guérin (BCG) vaccine. (G) H. influenzae type b, coverage with the third dose of H. influenzae type b vaccine (Hib3). (H) Hepatitis B, coverage with the third dose of hepatitis B vaccine (HepB).

Source: data from World Health Organization.

Figure 4.11 Certificate for the eradication of poliomyelitis in the WHO Western Pacific Region, 29 October 2000.

Figure 4.11
Certificate for the eradication of poliomyelitis in the WHO Western Pacific Region, 29 October 2000.

The poliomyelitis eradication initiative resulted in substantial investment in resources and had the effect of strengthening routine immunisation services in WPR member states (Alward, et al., 1997). This has contributed to a substantial decline in the incidence of diseases such as diphtheria (Figure 4.10A), pertussis (4.10C) and tetanus (4.10E), while new initiatives have followed. In 2003, the WPR Regional Committee Meeting established the twin goals of measles elimination (Figure 4.10B) and hepatitis B control (4.10H) by 2012. In addition, new and underutilised vaccines, including Hib (Figure 4.10G), pneumococcal, rotavirus and Japanese encephalitis vaccines, have been targeted for increased use (Clements, et al., 2006; WHO Western Pacific Region, 2008).

Beyond the EPI: Towards Second-Generation Programmes?

John, et al. (2011) suggest that one of the original objectives of the EPI, namely the development of vaccination programmes and sustainable infrastructure for their delivery in low- and middle-income countries, has been achieved. But the higher objective of the control of the EPI target diseases requires a second-generation programme that builds upon and subsumes the achievements of the EPI; a programme that has clear objectives to control a cluster of childhood diseases, and one whose outcomes are measured in terms of disease reduction rather than vaccine coverage. John, et al. (2011) propose that this second-generation programme could be named Control of Childhood Communicable Diseases (CCCD). CCCD would provide a platform for the integration of vertical disease control programmes from which to establish a public health infrastructure for childhood disease control in lower and middle-income countries. In addition to immunisation, such a programme would include: (i) the systematic reporting of diseases; (ii) the analysis and monitoring of diseases; (iii) the investigation of the occurrence of diseases that have been designated for control; and (iv) action to prevent, control and eliminate diseases and disease outbreaks.

4.5 National Programmes: Mass Vaccination and Disease Elimination in the United States

A review of immunisation in the United States is provided by Orenstein, et al. (2008). In this section, we examine how US programmes for the elimination of two major viral diseases of children, poliomyelitis and measles, have been articulated. Our account draws, in part, on Smallman-Raynor, et al. (2006, pp. 433–[link]) and Cliff, et al. (1993, pp. 217–[link]).

Poliomyelitis

The development and mass administration of safe and effective poliovirus vaccines has been one of the important public health achievements of the United States in the post-war era. The licensing of Salk’s inactivated poliovirus vaccine (IPV) in April 1955 marked the first specific federal involvement in immunisation (Orenstein, et al., 2008) and was accompanied by a dramatic reduction in disease incidence. But it was the introduction and mass administration of Sabin’s live attenuated oral poliovirus vaccine (OPV) from the early 1960s (Figure 4.1) that finally broke the chain of wild poliovirus transmission. Some impression of the scale and timing of the US vaccination programme required to effect the control of indigenous wild poliovirus is provided by Figure 4.12. In the words of Schonberger, et al. (1984, p. S424),

The successful control…involved the total net distribution of ∼483 × 106 doses of inactivated poliovirus vaccine (IPV), ∼114 × 106 doses of each of the three types of monovalent oral poliovirus vaccine (MOPV), and ∼423 × 106 doses of trivalent oral poliovirus vaccine (TOPV). Almost 90% of the IPV was distributed between 1955…and 1962 but as many as 5.5 × 106 doses were distributed in 1966, 4.0 × 106 doses in 1967, and 2.7 × 106 doses in 1968. About 93 percent of the doses of MOPV were distributed during 1962–1964, a fact that reflects the emphasis given to vaccinating both children and adults in mass vaccination campaigns and community-wide programs. Since the switch in 1965 to the current practice of routine vaccination of infants with TOPV, the annual distribution of TOPV has remained relatively stable, averaging ∼23 × 106 doses.

Figure 4.12 Annual number of doses of poliovirus vaccine distributed in the United States, 1954–81. Line traces plot the number of doses of inactivated poliovirus vaccine (IPV), monovalent oral poliovirus vaccine (MOPV) and trivalent oral poliovirus vaccine (TOPV). The annual count of poliomyelitis notifications is plotted as a bar chart.

Figure 4.12
Annual number of doses of poliovirus vaccine distributed in the United States, 1954–81. Line traces plot the number of doses of inactivated poliovirus vaccine (IPV), monovalent oral poliovirus vaccine (MOPV) and trivalent oral poliovirus vaccine (TOPV). The annual count of poliomyelitis notifications is plotted as a bar chart.

Source: redrawn from Smallman-Raynor, et al. (2006, Figure 10.5, p. 444), based on data in Communicable Disease Center (1964, [link]) and Centers for Disease Control (1982, Tables 2 and 7, [link], [link]).

The massive uptake of both IPV and OPV had an immediate and dramatic impact on the US poliomyelitis curve (Figure 4.13). The first year of immunisation with Salk vaccine resulted in a 47 percent reduction in notified cases, with a further 64 percent reduction in the following year. A decade or so later, in 1967, only 41 cases of poliomyelitis were reported throughout the United States, representing a decrease of 99.7 percent in notified cases since vaccination began. By January 1972, the incidence of the disease was deemed too low to justify the routine reporting of notifications in the flagship US disease surveillance report, Morbidity and Mortality Weekly Report (MMWR), while poliomyelitis associated with wild poliovirus – including importations – had fallen to near-zero levels by the early 1980s (Schonberger, et al., 1984).

Figure 4.13 Monthly count of poliomyelitis notifications in the conterminous United States, 1910–71. The years in which Salk’s inactivated poliovirus vaccine (IPV) and Sabin’s oral poliovirus vaccine (OPV) were first licensed in the United States are indicated.

Figure 4.13
Monthly count of poliomyelitis notifications in the conterminous United States, 1910–71. The years in which Salk’s inactivated poliovirus vaccine (IPV) and Sabin’s oral poliovirus vaccine (OPV) were first licensed in the United States are indicated.

The Geography of Vaccine-Induced Poliomyelitis Retreat, 1955–71

Between the onset of poliovirus vaccination in April 1955 and December 1971, some 70,300 cases of the disease were notified in the conterminous United States – a case total that was underpinned by annual epidemic upswings of rapidly diminishing magnitude to virtual extinction in the late 1950s and early 1960s (Figure 4.13). Figure 4.14 plots, as a monthly average, the state-level poliomyelitis notification rate per 100,000 population for April 1955–December 1971 (map D); the equivalent information for time intervals in the pre-vaccination phase (July 1910–March 1955, maps A–C) is shown for reference. From an established pattern of raised activity in the interval 1941–55, Figure 4.14D shows that the introduction of mass poliovirus vaccination was accompanied by a marked contraction in levels of poliomyelitis incidence. Average monthly case rates ≥ 0.5 per 100,000 population were limited to just a handful of states in the western United States (Arizona, Montana, Nevada, Utah and Wyoming).

Figure 4.14 Average monthly rate of poliomyelitis notifications (per 100,000 population) by state, conterminous United States, 1910–71. Map (D) plots the average monthly rate of poliomyelitis notifications for the vaccination phase (April 1955–December 1971). As a benchmark, Maps (A)–(C) plot the equivalent information for time intervals in the pre-vaccination phase (July 1910–March 1955).

Figure 4.14
Average monthly rate of poliomyelitis notifications (per 100,000 population) by state, conterminous United States, 1910–71. Map (D) plots the average monthly rate of poliomyelitis notifications for the vaccination phase (April 1955–December 1971). As a benchmark, Maps (A)–(C) plot the equivalent information for time intervals in the pre-vaccination phase (July 1910–March 1955).

Source: adapted from Smallman-Raynor, et al. (2006, Figures 7.3 and 10.6, pp. 270, 446).

Critical community size

In Section 4.3, we noted how the effect of vaccination is to raise the critical community size (CCS) required to maintain a target disease in endemic form. In the absence of vaccination, Eichner and colleagues (1994) have estimated the CCS for poliomyelitis to be of the order of 250,000 (range 50,000–500,000). Adopting a working estimate of 250,000, application of the computational procedure of Griffiths (1973) yields CCS estimates for poliomyelitis of 1 million (50 percent vaccination coverage; x = 0.5) and 25 million (90 percent vaccination coverage; x = 0.1) – estimates that are identical to those given for measles in Section 4.3. On this basis, it is possible to estimate the level of vaccination required to force the CCS for poliomyelitis above the population size of a given US state.

Figure 4.15 plots, on the horizontal axis, the estimated (minimum) level of vaccination coverage required to raise the CCS for poliomyelitis above the population size of each US state against, on the vertical axis, the first calendar year of the state-level time series (1955–71) with zero poliomyelitis notifications. Subject to the complicating factor of sub-clinical infection, the latter measure provides an indication of the year in which vaccination had forced the CCS above the population of a given state. For reference, circle sizes in Figure 4.15 are drawn proportional to the mid-period estimates of state populations.

Figure 4.15 Critical community size (CCS) and poliomyelitis vaccination in the United States. The graph plots, on the vertical axis, the year in which states first reported no poliomyelitis cases against, on the horizontal axis, the percentage vaccination coverage of the population required to achieve this. Circles are drawn proportional to state populations.

Figure 4.15
Critical community size (CCS) and poliomyelitis vaccination in the United States. The graph plots, on the vertical axis, the year in which states first reported no poliomyelitis cases against, on the horizontal axis, the percentage vaccination coverage of the population required to achieve this. Circles are drawn proportional to state populations.

Source: redrawn from Smallman-Raynor, et al. (2006, Figure 10.8, p. 449), originally from Nettleton (2002, Figure 7.21(a), p. 307).

Inspection of Figure 4.15 reveals, as we would expect, that the more populous states, which require higher estimated levels of vaccination coverage to achieve virus extinction, cross the empirically defined CCS threshold at relatively later dates than the less populous states implying that, from the early 1960s, poliomyelitis was progressively pinned back into a limited number of reservoir states with relatively large populations.

Poliomyelitis in a Heavily Vaccinated Population: The Last Cases (1972–88)

Between 1972 and the 1988 resolution of the Forty-First World Health Assembly to eradicate poliomyelitis globally, only two outbreaks of poliomyelitis were recorded in the United States. Both were associated with the spread of wild type 1 poliovirus in minority religious communities, and both were the consequence of residual pockets of susceptibility in an otherwise heavily vaccinated population. The first occurred in October 1972. It was associated with 11 cases of poliomyelitis (including 8 cases of paralysis) and was centred on Daycroft private boarding school at Greenwich, Connecticut, whose faculty and 128 students were Christian Scientists (Centers for Disease Control, 1974). As a remedial response to the demonstrably low vaccination coverage (46 percent) of the student population, vaccination of students, faculty members, and all other school employees was undertaken on 26–27 October. Other Christian Science families living in Greenwich, and whose children did not attend Daycroft School, were also contacted and administered trivalent OPV as required.

The second outbreak occurred in 1979 and was centred on members of a US Mennonite sect (Amish), some of whom reject immunisation on religious grounds. The outbreak first manifested in Pennsylvania (eight cases), with additional cases in Iowa (three cases), Wisconsin (three cases) and Missouri (one case); see Figure 4.16. The ultimate source of the virus was traced to a large epidemic of poliomyelitis among unvaccinated members of a Protestant sect of fundamentalist reformed churches (Netherlands Reformed Congregation) in the Netherlands in 1978, with the virus spreading to the United States via sect members in Canada (World Health Organization, 1978; Furesz, 1979; Centers for Disease Control, 1981). The outbreak illustrates how residual pockets of susceptibility can sustain chains of infection over long distances. We return to this theme in Section 4.6 with an analogous outbreak of measles among the Amish in 1987–88.

Figure 4.16 The 1979 outbreak of poliomyelitis among the Amish in the United States. (A) Vectors plot the diffusion of type 1 poliovirus in 1978 (Netherlands®Canada) and 1978–79 (Canada®USA). (B) Cases of poliomyelitis associated with the 1979 outbreak in the United States. Proportional circles show the number of poliomyelitis notifications by state. States in which Amish populations are resident have been shaded grey.

Figure 4.16
The 1979 outbreak of poliomyelitis among the Amish in the United States. (A) Vectors plot the diffusion of type 1 poliovirus in 1978 (Netherlands®Canada) and 1978–79 (Canada®USA). (B) Cases of poliomyelitis associated with the 1979 outbreak in the United States. Proportional circles show the number of poliomyelitis notifications by state. States in which Amish populations are resident have been shaded grey.

Source: redrawn from Smallman-Raynor, et al. (2006, Figure 10.16, p. 465).

The last cases of wild-virus poliomyelitis

Since the 1979 outbreak, all reported cases of disease due to wild poliovirus have been associated with importations from abroad (see, for example: Strebel, et al., 1992; Centers for Disease Control and Prevention, 1997b). During the period 1980–88, a total of five imported cases of wild-virus poliomyelitis were recorded in the United States – a rate of somewhat less than one case per year. Of the five cases, Mexico (two), Haiti (one), Nepal/Burma (one) and Zaire (one) were the presumed sources of infection, with the disease occurring in three travellers and two recent immigrants. No secondary cases of disease were attributed to the imported cases. The fifth and final case in the series, detected in 1986, was the last confirmed case of wild-virus poliomyelitis in the United States (Strebel, et al., 1992; Centers for Disease Control and Prevention, 1995). On the basis of the five documented cases of wild-virus disease, and with an assumed infection-to-paralytic case ratio of 200:1, Strebel, et al. (1992, p. 575) estimate that the average number of wild poliovirus importations (clinical and sub-clinical) was of the order of 100 per year in the 1980s.

Vaccine-associated paralytic poliomyelitis (VAPP)

Poliomyelitis due to live vaccine strains of poliovirus, manifesting in vaccine recipients or through virus transmission to their contacts, may represent the predominant form of the disease when levels of wild-virus infection are low. In the United States, vaccine-associated paralytic poliomyelitis (VAPP) has been the principal form of the disease since 1973 and, with one possible exception, the only form since 1986 (Strebel, et al., 1992). Between the mid-1960s and the late 1980s, the level of VAPP remained approximately constant at 3–4 cases per 10 million doses of OPV distributed. As Table 4.6 shows, 83 cases of VAPP were recorded in the United States in the period 1980–88, with an approximately equal distribution between (i) vaccine recipients (43 cases) and (ii) contacts of vaccine recipients (40 cases).

Table 4.6 Number of cases of vaccine-associated paralytic poliomyelitis (VAPP) in the United States, 1980–88

Exposure category

Cases

Vaccine recipients

43

Immunologically normal

33

Immunologically compromised

10

Contacts of vaccine recipients

40

Immunologically normal

35

Immunologically compromised

5

Total

83

Source: information from Centers for Disease Control and Prevention (1997a, Table 1, [link]).

Measles

In the early years of the twentieth century, thousands of deaths were caused by measles in the United States each year and, at mid-century, an annual average of more than 0.5 million cases and nearly 500 deaths were reported. It was against this background of great need and vaccine availability that the US Centers for Disease Control (CDC) evolved in the United States a programme for the elimination of indigenous measles once a safe and effective vaccine was licensed for use in 1963 (Appendix 4.1). In 1966, CDC announced that the epidemiological basis existed for the elimination of indigenous measles from the United States. This was the first of three measles elimination drives to be implemented in the latter part of the twentieth century (Figure 4.17), each consisting of the basic strategies of high vaccination coverage among preschool and school-aged children, case surveillance and outbreak control.

Figure 4.17 Measles reduction in the United States. (A) Annual reports of measles cases, 1939–2009. (B) Annual reports of measles cases 1961–2009 (solid line trace) and population coverage with measles-containing vaccines 1967–2009 (pecked line trace). Periods associated with elimination initiatives are identified by the grey shading. Note that pre-1993 immunisation data relate to children aged 24 months (National Immunization Survey), while later data relate to children aged 19–35 months (National Immunization Program and the National Center for Health Statistics, CDC).

Figure 4.17
Measles reduction in the United States. (A) Annual reports of measles cases, 1939–2009. (B) Annual reports of measles cases 1961–2009 (solid line trace) and population coverage with measles-containing vaccines 1967–2009 (pecked line trace). Periods associated with elimination initiatives are identified by the grey shading. Note that pre-1993 immunisation data relate to children aged 24 months (National Immunization Survey), while later data relate to children aged 19–35 months (National Immunization Program and the National Center for Health Statistics, CDC).

Source: data from Centers for Disease Control and Prevention (CDC).

The First Elimination Drive (1966–70)

Following the announcement of possible measles elimination in 1966, considerable effort was put into mass measles immunisation programmes throughout the United States. To achieve elimination, the immunisation of 90–95 percent of the childhood population was aimed for (i.e. herd immunity). Federal funds were appropriated and, over the next three years, an estimated 20 million doses of vaccine were administered. The discontinuity induced in the national time-series of reported cases is shown in Figure 4.17A. In 1962, the year before measles vaccine was introduced, there were over 481,500 cases of measles reported in the United States. Within four years, this figure had been halved and, within six years, the reported incidence had plummeted to only 22,000. In 1969, however, emphasis shifted to the administration of the newly-licensed rubella vaccine (Table 4.2) and, by the following year, federal funding for measles vaccination had ceased. One determining factor in the ultimate fate of the elimination drive was its failure to achieve and sustain high levels of immunisation in preschool-aged children. So, as Figure 4.17B shows, annual coverage of two-year-olds did not exceed 62 percent in the latter years of the 1960s. Moreover, less than 50 percent of states had school immunisation requirements which would ensure the objective of high immunisation coverage at school entry (Hinman, et al., 2004).

The Second Elimination Drive (1978–88)

Measles soon began to rebound. To remedy the situation, a nationwide Childhood Immunisation Initiative was launched in April 1977, followed by the announcement of a programme to eliminate indigenous measles from the United States within five years (the ‘Make Measles a Memory’ campaign). The immunisation goal was again 90–95 percent of the childhood population. The geographical impact of this second push against the disease is seen in Figure 4.18. The maps show the distribution of counties in the United States reporting measles cases at the start of the campaign (1978, Figure 4.18A) and five years later in 1983 (4.18B). The contraction of infection from most of the settled parts of the United States in 1978 to restricted areas of the Pacific Northwest, California, Florida, the northeastern seaboard and parts of the Midwest is pronounced. The persistence of indigenous measles in many of these regions may be explained by the importation of cases from Mexico and Canada. By 1983, 12 states and the District of Columbia reported no measles cases, and 26 states and the District of Columbia reported no indigenous cases.

Figure 4.18 The geographical distribution of measles in the United States, 1978–2011. Counties reporting cases of measles in (A) 1978, (B) 1983 and (C) 1993. Map D plots the distribution and source (import associated or unknown) of reported measles cases, 1 January–20 May 2011.

Figure 4.18
The geographical distribution of measles in the United States, 1978–2011. Counties reporting cases of measles in (A) 1978, (B) 1983 and (C) 1993. Map D plots the distribution and source (import associated or unknown) of reported measles cases, 1 January–20 May 2011.

Source: maps (A) and (B) redrawn from Cliff and Haggett (1988, Figures 4.9(C) and (D), [link]); map (C) redrawn from Centers for Disease Control and Prevention (1993a, [link]); map (D) redrawn from Centers for Disease Control and Prevention (2011a, Figure 1, p. 666).

The second elimination drive failed to achieve its goal by the target date of 1 October 1982 and measles incidence began to rise once again. This major resurgence was associated with 55,685 reported cases, 11,000 hospital admissions and 123 deaths in 1989–91 (Figure 4.17B). This resurgence was part of a more general upturn in disease activity in the Western Hemisphere which had resulted in the importation of hundreds of cases into the US. The principal causes of this epidemic were vaccine failure among a small proportion of school-aged children who had received one dose of measles vaccine, and low vaccine coverage among preschool-aged children (Hinman, et al., 2004; Orenstein, et al., 2004).

The Third Elimination Drive (1993–96)

Following the measles resurgence of 1989–91, a new childhood immunisation initiative was implemented in 1993 that included a call for the elimination of six vaccine-preventable diseases (including measles) by 1996. The geographical distribution of measles cases at the start of the third drive is shown in Figure 4.18C. The elimination strategy involved four elements: (i) to maximise population immunity through vaccination, including the timely immunisation of preschool-aged children and the delivery of a second dose of measles vaccine to school children; (ii) to ensure adequate surveillance; (iii) rapid outbreak response; and (iv) to work in partnership with other countries towards the achievement of global measles control. As Figure 4.17B shows, the annual count of notified measles cases had fallen to just 500 in 1996 and, by the end of the decade, to less than 100 (Hinman, et al., 2004).

The interruption of endemic measles transmission

In March 2000, the National Immunization Program of CDC convened a meeting to assess whether measles was currently endemic in the United States. It was recognised that elimination of endemic disease does not require a total absence of indigenous cases; rather, it requires the absence of continuing indigenous transmission. The implication is that the disease can be eliminated as an indigenous condition even though recurrent outbreaks still occur. In the period 1997–99, a total of 338 measles cases (< 1 case per million population) were recorded. Of these, 34 percent were imported, 30 percent were epidemiologically linked to an imported case or were caused by an imported virus genotype, while the remaining 36 percent had an unknown source. The reproductive rate of measles, R, was estimated at < 0.8 in the period 1997–99, with molecular data supporting the proposition that endemic measles virus transmission had been interrupted in the country. R is defined in its basic form, R0, in Section 6.2. Here, it is sufficient to note that, when R > 1.0, each measles case generates an average of more than one secondary case, thereby resulting in an increase in cases and sustained transmission of measles virus. Conversely, when R < 1.0, the measles transmission chain will be broken. On the basis of information available, the meeting concluded that measles was not currently endemic in the United States (Katz and Hinman, 2004).

The continuing problem of measles importation

Over a decade after the declaration of the interruption of sustained indigenous measles virus transmission in the United States, imported cases of the disease continue to occur. In the period 1 January–20 May 2011, for example, 118 measles cases were reported from 23 states and New York City – the highest reported number in the period since 1996 (Figure 4.18D). The majority of these (105 cases) were acquired directly or indirectly from abroad, and 9 outbreaks were recorded. The largest of the outbreaks (21 cases) was in Minnesota and occurred among children who were unvaccinated owing to concerns over the safety of the combined measles, mumps and rubella (MMR) vaccine (Centers for Disease Control and Prevention, 2011a). We return to the implications of declining immunity arising from the MMR vaccine scare, with special reference to the United Kingdom, in Section 4.6.

Economic Evaluations of Vaccination Programmes

Economic analyses of vaccine policies are reviewed by Miller and Hinman (2008). Over the years, decisions about the use of vaccines and their incorporation into routine immunisation schedules have been increasingly informed by economic evaluations of their relative costs (inputs) and benefits (outcomes) as public health interventions (Szucs, 2000). Costs are ordinarily assessed in terms of the monetary investment in vaccines and their delivery, manpower and programme administration, and the costs of the treatment of vaccine side effects. Benefits are typically measured in terms of the healthcare savings that accrue from morbidity and mortality averted. Here, we briefly summarise the results of sample cost–benefit studies in relation to the poliomyelitis and measles elimination campaigns in the United States.

Poliomyelitis elimination. Beginning with the onset of mass vaccination with IPV in 1955, and projected through to 2015, Thompson and Duintjer Tebbens (2006) estimate the investment of the United States in poliovirus vaccines at US$2002 36.4 billion. In the same 60-year interval, 1.7 billion doses of vaccine will have been delivered, resulting in the prevention of 1.1 million cases of paralytic poliomyelitis (including > 160,000 deaths) and yielding, net of treatment costs, economic benefits of almost US$2002 180 billion.

Measles elimination. Taking a hypothetical 2001 US birth cohort of approximately 3.8 million and following the cohort to age 40 years, Zhou, et al. (2004) estimate that the two-dose MMR vaccine strategy adopted as part of the 1990s elimination drive would avert 3.4 million measles cases, 2.1 million mumps cases and 1.8 million rubella cases, 616 cases of congenital rubella syndrome (CRS) and 2,888 deaths as compared to a no-vaccination scenario. The net savings of the two-dose programme from direct costs are estimated at US$2001 3.5 billion, with every US$ spent on the programme yielding savings of > US$14 in direct costs and > US$10 in additional costs to society. While the delivery of the second dose of MMR vaccine was not judged by Zhou and colleagues to yield net economic savings, this component of the two-dose strategy is acknowledged to have been pivotal to the interruption of indigenous measles.

4.6 Vaccination Risks

Faulty Vaccines

Vaccines are not risk-free (Offit, et al., 2008). Ever since the early work on smallpox vaccination, adverse events have been shown to follow their administration. Sometimes manufacturing faults may result in the very diseases against which they are supposed to protect. Or the vaccines may unwittingly contain other pathogenic microorganisms that cause disease outbreaks (for example, Anonymous, 1942a, b on jaundice following yellow fever vaccination). Vaccines may also cause severe adverse events that are not associated with faulty production. Examples include poliovirus vaccine-associated paralytic poliomyelitis (Table 4.6) and Guillain–Barré syndrome following the receipt of swine influenza A vaccine (Offit, et al., 2008). Here, we illustrate what may happen with faulty vaccine manufacture using the well-known Cutter incident which occurred in the early history of the US poliomyelitis vaccination campaigns (Section 4.5) and which were based upon Salk’s inactivated poliovirus vaccine (IPV).

Poliomyelitis and the Cutter Incident

A national US vaccination programme with the newly licensed IPV had begun on 12 April 1955, with approximately four million doses of the vaccine – manufactured by five different pharmaceutical companies – having been administered to first- and second-grade children across the Union in less than four weeks (Paul, 1971; Blume and Geesink, 2000). But the nascent vaccination programme was called to a sudden halt in early May 1955. Between 18 and 27 April, some 400,000 inoculations with batches of vaccine manufactured by Cutter Laboratories of Berkeley, California, had been administered to the general public, of which an estimated 120,000 were drawn from production pools that contained residual live poliovirus. When cases of poliomyelitis began to appear among recipients of the defective vaccine, Leonard A. Scheele, Surgeon General, requested the manufacturer to recall all outstanding lots of vaccine on Wednesday 27 April. Ten days later, on Saturday 7 May, Scheele recommended a complete suspension of the vaccination programme pending a full assessment of the safety of the vaccines (Langmuir, et al., 1956; Nathanson and Langmuir, 1963a, b).

The Cutter incident was associated with 158 notified cases of paralytic poliomyelitis, with the histograms in Figure 4.19 showing a time-ordered sequence of the appearance of paralysis in each of three exposure categories. The first cases of paralytic disease were recorded in vaccine recipients on 22–23 April (Figure 4.19A), with cases subsequently appearing in family (30 April; Figure 4.19B) and community (12 May; Figure 4.19C) contacts. The majority of cases of paralysis occurred within a month of the recall of defective vaccine (27 April). Geographically, Figure 4.20 shows that cases were centred on the states of California (57 paralytic cases) and Idaho (49 paralytic cases) and reflected the unwitting distribution of defective vaccine by the National Foundation for Infantile Paralysis to school clinics in these states. Defective lots of Cutter vaccine were also used in school clinics in Nevada, Arizona, New Mexico and Hawaii, while the remaining scattered cases were associated with vaccine that had been distributed through commercial channels (Langmuir, et al., 1956).

Figure 4.19 Time series of paralytic poliomyelitis associated with the Cutter incident, April–June 1955. Histograms plot, by day of onset of paralysis, the number of recorded cases of poliomyelitis associated with the administration of vaccine manufactured by Cutter Laboratories, California. (A) Cases among vaccine recipients. (B) Cases among family contacts of vaccine recipients. (C) Cases among community contacts of vaccine recipients and their family contacts.

Figure 4.19
Time series of paralytic poliomyelitis associated with the Cutter incident, April–June 1955. Histograms plot, by day of onset of paralysis, the number of recorded cases of poliomyelitis associated with the administration of vaccine manufactured by Cutter Laboratories, California. (A) Cases among vaccine recipients. (B) Cases among family contacts of vaccine recipients. (C) Cases among community contacts of vaccine recipients and their family contacts.

Source: Smallman-Raynor, et al. (2006, Figure 10.2, p. 439), originally redrawn from Langmuir, et al. (1956, Figure 1, [link]).

Figure 4.20 Geographical distribution of cases of poliomyelitis associated with the Cutter incident, April–June 1955. Circle areas are drawn proportional to the total number of cases of poliomyelitis recorded in a given state. The proportion of cases in which paralysis was observed is indicated by the shaded sectors.

Figure 4.20
Geographical distribution of cases of poliomyelitis associated with the Cutter incident, April–June 1955. Circle areas are drawn proportional to the total number of cases of poliomyelitis recorded in a given state. The proportion of cases in which paralysis was observed is indicated by the shaded sectors.

Source: Smallman-Raynor, et al. (2006, Figure 10.3, p. 440), drawn from data in Langmuir, et al. (1956, Table 1, [link]).

Cutter Laboratories was not the only manufacturer to experience difficulties in the production of IPV. Coincidental with the Cutter outbreak, a small number of poliomyelitis cases were reported among children in Pennsylvania and Maryland who had received vaccine manufactured by Wyeth Inc. of Philadelphia. But the interruptions caused by the defective Cutter and Wyeth vaccines were relatively brief and, by June, the national vaccination campaign with IPV had resumed (Langmuir, et al., 1956).

False Alarms and Declining Herd Immunity

Occasionally, unfounded or unproven health concerns have shaken public confidence in vaccines. In the 1970s, for example, widely publicised concerns over the safety of pertussis vaccines (including an alleged association with permanent neurological damage that was never demonstrated conclusively; see Baker, 2003) resulted in a dramatic reduction in vaccine uptake in some countries of Europe, North America and elsewhere, with a consequent resurgence of the disease. The MMR controversy in the United Kingdom and oral poliovirus vaccine (OPV) in Nigeria provide more recent examples of the phenomenon and its potential epidemiological consequences.

Developed Countries: The MMR Controversy in the United Kingdom

Although combined measles, mumps and rubella (MMR) vaccine had been licensed in the United States as early as 1971 (Table 4.2), the adoption of the combined vaccine as part of the routine childhood immunisation schedule in the United Kingdom awaited the late 1980s. Following successful trials in three health districts (two in England, one in Scotland), national introduction of combined MMR vaccine took place in October 1988 with a target to achieve 90 percent immunisation coverage of children by their second birthday. At the time of the introduction of the MMR vaccine, the measles and rubella components were already in general use in Britain in their monovalent forms, while the mumps vaccine had been licensed for some years. When it was introduced, the triple MMR vaccine had a substantial effect on the three target diseases, notably measles for which available evidence indicated the sustained interruption of indigenous virus transmission by the late 1990s (Ramsay, et al., 2003).

In a controversial paper published in The Lancet in 1998, Andrew Wakefield and colleagues described a series of children with developmental disorders that had been referred to the Royal Free Hospital, London, and which pointed to an apparent association between the MMR vaccine and autism. Although subsequent studies in the United States and the United Kingdom failed to identify a link between the MMR vaccine and autism, and Wakefield’s original paper was fully retracted by The Lancet in 2010, fears over the safety of the MMR vaccine resulted in reduced vaccine uptake to levels well below those required for herd immunity for the target diseases. From a high of 92 percent in the mid-1990s, MMR vaccine coverage among two-year-olds in England and Wales fell to just 80 percent in 2003–4, 15 percent below the WHO-recommended level for herd immunity (Asaria and MacMahon, 2006). Amid increased calls for a change in national immunisation policy that permitted parents to choose between the triple MMR and single vaccines, measles and mumps re-emerged in epidemic form in the early twenty-first century (Figure 4.21).

Figure 4.21 Measles and mumps in England and Wales, January 1995–September 2010. Bar charts plot the quarterly count of laboratory-confirmed cases. The quarterly counts for 2010 are based on provisional data. The proportion of the population that had received measles, mumps and rubella (MMR) vaccine at two years of age is plotted as the line traces. (A) Measles. (B) Mumps. The WHO-recommended level of 95 percent vaccine coverage for disease elimination (herd immunity threshold) is indicated. In February 2005, at the height of the 2004–5 mumps epidemic, the HPA temporarily halted the laboratory testing of notified cases in the 1981–86 birth cohort. Testing was resumed in January 2006. The case totals for 2005 in graph (B) therefore exclude a large number of cases that would otherwise have been confirmed by laboratory testing.

Figure 4.21
Measles and mumps in England and Wales, January 1995–September 2010. Bar charts plot the quarterly count of laboratory-confirmed cases. The quarterly counts for 2010 are based on provisional data. The proportion of the population that had received measles, mumps and rubella (MMR) vaccine at two years of age is plotted as the line traces. (A) Measles. (B) Mumps. The WHO-recommended level of 95 percent vaccine coverage for disease elimination (herd immunity threshold) is indicated. In February 2005, at the height of the 2004–5 mumps epidemic, the HPA temporarily halted the laboratory testing of notified cases in the 1981–86 birth cohort. Testing was resumed in January 2006. The case totals for 2005 in graph (B) therefore exclude a large number of cases that would otherwise have been confirmed by laboratory testing.

Source: redrawn from Smallman-Raynor and Cliff (2012, Figure 11.5, [link]), based on data from the Health Protection Agency (HPA).

Measles

Levels of susceptibility to measles grew rapidly. Starting from a position in which indigenous measles virus transmission had been effectively eliminated, 1.9 million school children and 0.3 million preschool children were estimated to be incompletely vaccinated against measles in England by 2004–5. Of these, approximately 1.3 million children aged 2–17 years were deemed susceptible to the disease. Fourteen of the 99 districts and strategic health authorities of England, including 11 London districts, had levels of susceptibility that were sufficiently high to support sustained measles virus transmission, while mathematical modelling pointed to the potential for a measles epidemic of up to 100,000 cases (Hong Choi, et al., 2008). Informed by these estimates, the Health Protection Agency (HPA) announced in June 2008 that the number of susceptible children was sufficient to support the continuous transmission of measles virus and that the disease was once again endemic in the United Kingdom (Health Protection Agency, 2008).

Geographically, the decline in MMR vaccine uptake was especially pronounced in London (Figure 4.22), where levels of susceptibility among school children were deemed sufficiently high to support a London-wide epidemic in 2004–5 (Figure 4.23). In response, the MMR Capital Catch-up Campaign was launched with the aim of delivering one dose of MMR vaccine to children of primary school age with an incomplete vaccination history. Despite these efforts, measles has continued to spread in parts of the capital. A range of socio-economic factors are believed to have contributed to the low vaccine uptake, including high population mobility and family size, while anecdotal evidence suggests that some parents made an active decision not to have their children immunised.

Figure 4.22 Uptake of MMR vaccine, London and the United Kingdom, 1996–2005. Uptake is shown for children at two years of age. The WHO-recommended level of vaccine coverage for measles elimination (95 percent) is represented by the grey horizontal pecked line. While MMR uptake in the United Kingdom (solid line trace) fell steadily from 1997, the decline was most pronounced in London (broken line trace).

Figure 4.22
Uptake of MMR vaccine, London and the United Kingdom, 1996–2005. Uptake is shown for children at two years of age. The WHO-recommended level of vaccine coverage for measles elimination (95 percent) is represented by the grey horizontal pecked line. While MMR uptake in the United Kingdom (solid line trace) fell steadily from 1997, the decline was most pronounced in London (broken line trace).

Source: redrawn from Smallman-Raynor and Cliff (2012, Figure 11.6, [link]), originally from the Health Protection Agency (2006, Figure 4, [link]).

Figure 4.23 Estimated potential for measles virus transmission in districts of London, 2004. The potential for measles virus transmission (assessed according to levels of susceptibility in the population) is summarised by the effective reproduction number, R. For the majority of London districts R > 1.0, sufficient to generate a London-wide epidemic of measles.

Figure 4.23
Estimated potential for measles virus transmission in districts of London, 2004. The potential for measles virus transmission (assessed according to levels of susceptibility in the population) is summarised by the effective reproduction number, R. For the majority of London districts R > 1.0, sufficient to generate a London-wide epidemic of measles.

Source: redrawn from Smallman-Raynor and Cliff (2012, Figure 11.9, [link]), originally from the Health Protection Agency (2006, Figure 8, [link]).

Mumps

The resurgence of mumps in the early twenty-first century (Figure 4.21B) was a predictable consequence of gaps in eligibility for MMR vaccine that resulted in a cohort of mumps-susceptible children who progressed through secondary school and beyond in the early 2000s. Many were born prior to the implementation of a two-dose MMR programme and they had consequently received only one or no doses of MMR vaccine, thereby creating a pool of susceptibility when they entered university and college settings (Savage, et al., 2005, 2006). The resulting mumps epidemic of 2004–5 spread nationwide and was associated with some 70,000 notified cases (Figures 4.24A and B). Frequent occurrence of severe complications was a prominent feature of the epidemic. A subsequent epidemic of mumps was observed in 2008–9 and was again associated with several outbreaks in universities and colleges (Figure 4.24C). The lag between the 2004–5 and 2008–9 epidemics may be accounted for by the fact that, since the 2004–5 epidemic, three new cohorts of students had entered the higher education sector, thereby re-establishing a susceptible pool in the confined setting of lecture rooms and halls of residence (Anonymous, 2009).

Figure 4.24 Mumps in England and Wales. Maps plot the notified case rate per 100,000 population by Strategic Health Authority for the epidemic years 2004, 2005 and 2009.

Figure 4.24
Mumps in England and Wales. Maps plot the notified case rate per 100,000 population by Strategic Health Authority for the epidemic years 2004, 2005 and 2009.

Source: redrawn from Smallman-Raynor and Cliff (2012, Figure 11.10, [link]), based on data from the Health Protection Agency (HPA).

Developing Countries: Local Cultures and Polio Vaccine Uptake in Nigeria

As described in Section 5.3, the historic resolution that committed the WHO to the global eradication of poliomyelitis was adopted by the Forty-First World Health Assembly in May 1988. This goal was endorsed by the Committee of the WHO Regional Office for Africa in 1989. Eradication activities in Africa were rapidly expanded in 1996 and 1997 so that, by early 1998, most countries of the region had conducted full-scale national immunisation days (NIDs); many countries had established acute flaccid paralysis (AFP) surveillance systems, while a functional regional laboratory network had also been created (World Health Organization, 1998a).

Some impression of progress towards the interruption of wild poliovirus transmission in the African Region can be gained from Figure 4.25A. As the heavy line trace shows, the median reported level of coverage of infants with three doses of poliovirus vaccine increased from 48 percent (1988) to 79 percent (2003), with a corresponding reduction in the number of notified cases of poliomyelitis (bar chart). But marked subregional variations in levels of vaccination coverage persisted throughout the period, with relatively high coverage in the subregions of east and south Africa and relatively low coverage in central and west Africa (Figure 4.25B). These variations, in turn, resulted in geographical differences in the timing of poliomyelitis retreat in the African Region. From a base-line position of region-wide endemicity in 1988, endemic activity had ceased in many countries of south Africa by 1994 and east Africa by 1997. By 2002, the disease had been driven out of central Africa while, by 2003, only two countries of the Africa Region (Niger and Nigeria) continued to report the endemic transmission of wild poliovirus.

Figure 4.25 Poliomyelitis cases and poliovirus vaccination in the WHO Africa Region, 1966–2003. (A) Annual count of reported cases in the Africa Region (bar chart) and median reported level of national coverage of infants with three doses of poliovirus vaccine (line trace), 1966–2003. (B) Median reported level of national coverage of infants with three doses of poliovirus vaccine in the member states of the WHO Africa subregions, 1988–2003.

Figure 4.25
Poliomyelitis cases and poliovirus vaccination in the WHO Africa Region, 1966–2003. (A) Annual count of reported cases in the Africa Region (bar chart) and median reported level of national coverage of infants with three doses of poliovirus vaccine (line trace), 1966–2003. (B) Median reported level of national coverage of infants with three doses of poliovirus vaccine in the member states of the WHO Africa subregions, 1988–2003.

Source: redrawn from Smallman-Raynor, et al. (2006, Figures 12.5A and 12.9, pp. 581, 592), originally based on data from WHO Vaccines, Immunization and Biologicals (2005).

Nigeria and the decline in poliovirus vaccine uptake

The Global Polio Eradication Initiative was confronted with a number of unprecedented challenges in 2003. Foremost among these was the decision of several Nigerian states – including the northern states of Kaduna, Kano, Niger and Zamfara – temporarily to suspend all supplementary immunisation activities because of rumours over the safety of OPV. While the safety of the vaccine was confirmed to the satisfaction of most parties in March 2004, and the majority of Nigerian states endorsed the resumption of participation in immunisation activities, the suspensions were associated with a marked increase in the level and geographical extent of poliovirus activity. Between 2002 and 2003, the annual count of confirmed cases of wild poliovirus in Nigeria increased from 202 to 355, while the number of infected states swelled from 15 to 23 (World Health Organization, 2004a, d).

While outbreaks of poliovirus type 3 were recorded in Nigeria in 2003 (World Health Organization, 2004a), it was the upsurge in poliovirus type 1 that was to pose the gravest threat to the Global Polio Eradication Initiative. The maps in Figure 4.26 relate to the primary surviving genotype of wild poliovirus type 1 in Africa (West Africa-B, or WEAF-B, genotype) and plot the geographical distribution of isolations by year, 2001–3. From an initial focus in northern and central Nigeria and southern Niger in 2001–2, the vectors in Figure 4.26C show that, during 2003, the virus spread beyond the borders of the reservoir states into eight adjacent countries – each of which had been free of indigenous wild poliovirus for at least two years. Notwithstanding the vigorous implementation of vaccination in all eight countries, the net result of the continuing spread of poliovirus was the re-establishment of wild virus transmission in four countries (Burkina Faso, Central African Republic, Chad and Côte d’Ivoire). In recognition of the gravity of the situation, health ministers of the African Union resolved that 22 west and central African countries should launch emergency synchronised immunisation activities – at an additional cost of US$100 million – in 2004–5 (World Health Organization, 2004b, c).

Figure 4.26 Geographical spread of wild poliovirus type 1, West Africa-B (WEAF-B) genotype, Africa, 2001–3. Maps plot the distribution of isolates in (A) 2001, (B) 2002 and (C) 2003. The vectors in map (C) indicate the likely routes of transmission of poliovirus from the Nigerian reservoir in 2003.

Figure 4.26
Geographical spread of wild poliovirus type 1, West Africa-B (WEAF-B) genotype, Africa, 2001–3. Maps plot the distribution of isolates in (A) 2001, (B) 2002 and (C) 2003. The vectors in map (C) indicate the likely routes of transmission of poliovirus from the Nigerian reservoir in 2003.

Source: redrawn from Smallman-Raynor, et al. (2006, Figure 12.10, p. 595), adapted from maps in Global Polio Eradication Initiative Virologic Analysis of Serotype 1 (PV1), West Africa-B (WEAF-B) Genotype Monthly Reports (June 2003 and April/May 2004), courtesy of Paul Chenoweth, CDC.

The spread of wild poliovirus type 1 from Nigeria to other states of west and central Africa marked the first phase of an international spread process that, in 2004–5, extended beyond the strictly defined limits of the Africa Region to include the WHO Eastern Mediterranean (Sudan and Yemen) and South-East Asia (Indonesia) Regions (Figure 4.27). The ramifications of the loss in public confidence in OPV in northern Nigeria in 2003, combined with the country’s weak public health system infrastructure and programmatic limitations, continue to be felt by the Global Polio Eradication Initiative. Between 2003 and 2011, wild polioviruses of Nigerian origin had been imported into 25 countries, with repeated importations into many countries of west and central Africa (World Health Organization, 2011c).

Figure 4.27 The international transmission of West African-related genotypes of wild poliovirus type 1 to Sudan and beyond, 2004–5. Vectors plot the corridors of virus transmission from an imputed origin in west Africa. Bar charts show the number of cases of wild poliovirus detected in infected localities in 2004 and 2005 (1 January–21 June).

Figure 4.27
The international transmission of West African-related genotypes of wild poliovirus type 1 to Sudan and beyond, 2004–5. Vectors plot the corridors of virus transmission from an imputed origin in west Africa. Bar charts show the number of cases of wild poliovirus detected in infected localities in 2004 and 2005 (1 January–21 June).

Source: redrawn from Smallman-Raynor, et al. (2006, Figure 12.19, p. 616), originally based on information in World Health Organization (2005b, c, d).

Spatially Heterogeneous Vaccination Uptake

As noted in Section 4.5, religious groups exempt from immunisation laws form a small but significant risk group for outbreaks of infectious diseases in otherwise highly vaccinated populations. Special epidemiological interest attaches to US Mennonite (Amish) communities. The Amish migrated to the United States in 1709 to escape religious persecution, with the first settlements founded in Pennsylvania. By the late 1970s, Amish communities were located in more than 20 states of the Union, with the total population numbering some 75,000. As Cliff, et al. (1993, p. 239) observe, several characteristics of the Amish predispose them to epidemics of common infectious diseases, of which the rejection of immunisation by some sect members is pertinent to the events to be described. When coupled with the high level of national and international socialisation of the Amish and related sects, spatially separated pockets of susceptibility can sustain disease transmission chains over large (occasionally inter-continental) distances and for extended periods of time. Such was the case for the last recorded outbreak of wild poliovirus in the United States in 1979 (Section 4.5) and, as illustrated here, the analogous events associated with a measles outbreak in 1987–88 (Cliff, et al., 1993, pp. 239–[link]).

The Amish measles outbreak of 1987–88 had its origin in Lawrence County, Pennsylvania – a county in which no cases of measles had been reported from 1970 until the onset of the outbreak on 5 December 1987 (Figure 4.28). The first two cases connected to the outbreak were students from Neshannock school district in Lawrence and their source of exposure to measles virus is unknown. The subsequent sequence of spread among the Pennsylvania Amish is reconstructed in Figure 4.28A. On 21 March 1988, the first cases were reported among Amish students in Mercer County. One virus generation later, measles had reached Indiana and Mifflin Counties. On 4 April, a group of Amish from Lebanon County visited an Amish family in Mifflin County and had contact with a measles patient. Of the visiting group, eight contracted measles from the patient. The disease then spread rapidly through other Amish families in Lebanon so that, by 30 June, 130 cases among 25 Amish families in the county had occurred in some five virus generations. The crude attack rate was 39 percent, and 74 percent among those susceptible to measles. Amish families in other Pennsylvanian counties also became involved so that, by 30 July 1988, cases were reported among the Amish from 13 counties.

Figure 4.28 Pennsylvania measles outbreak, 1987–88: spread in the Amish community. (A) Dates of rash onset of the first Amish case in each county, 1988; vectors identify diffusion routes. (B) Date of rash onset among Amish patients in Lebanon County by exposure status, 1988. (C) Spread to Amish communities in other states, 1988.

Figure 4.28
Pennsylvania measles outbreak, 1987–88: spread in the Amish community. (A) Dates of rash onset of the first Amish case in each county, 1988; vectors identify diffusion routes. (B) Date of rash onset among Amish patients in Lebanon County by exposure status, 1988. (C) Spread to Amish communities in other states, 1988.

Source: redrawn from Cliff, et al. (1993, Figure 9.15, p. 240), based on data from Sutter, et al. (1991, Figure 1 and text, [link]).

To control the outbreak, special measles vaccination clinics were held in locations convenient to the Amish (schools and homes). In Lebanon County, two clinics were held in May 1988, but attendance was poor and only 14 Amish were vaccinated. Measles spread from the Pennsylvania Amish to other Amish communities in Kentucky (April), Michigan (June), New York (July) and Ohio (September); see Figure 4.28C. All were linked epidemiologically to the Pennsylvania outbreak (Sutter, et al., 1991).

The outbreak illustrates several important themes: the role of schools as diffusion poles, leading to geographically contagious spread; the susceptibility to high attack rates of isolated but linked communities once infection occurs; and the impact of vaccination levels upon the spread of measles. From the viewpoint of measles elimination in the United States, described in Section 4.5, it demonstrates the potential reservoir for virus survival provided by difficult-to-reach, unvaccinated groups. These may be religious sects as discussed here, mobile communities such as gypsies and itinerant populations (Smallman-Raynor, et al., 2006, p. 496) and inner city ethnic groups (for example, the Latinos in Los Angeles studied by Ewert, et al., 1991).

4.7 Conclusion

The range of diseases that can be prevented by routine immunisation has expanded in the post-war decades. In addition to vaccines against the common infectious killers of childhood, vaccines to prevent diseases in later life, including hepatitis B (liver cancer) and human papilloma virus (cervical cancer) vaccines, have been added to the routine infant immunisation schedules of a number of countries. Vaccines for malaria are under development, as are improved vaccines against tuberculosis, while vaccination against HIV may one day be possible. As for the future, Greenwood, et al. (2011, pp. 2733–4) observe that:

If the full, global potential of vaccination is to be achieved, advances must be made in three main areas. Firstly, the fundamental science that leads to new ways of designing vaccines and of delivering them more effectively needs increased support. Secondly, transition of new discoveries in the laboratory into practical vaccines needs to be accelerated. Thirdly, mechanisms need to be developed which make existing vaccines, and the increasing number of new vaccines on the horizon, available to those who need them most, ensuring that every child is reached and that vaccination provides protection for life and not just for childhood.

The development of new vaccines in the early twenty-first century is an expensive process, costing an estimated US$500–1,000 million from first concept to licensed product. There may be as many as 20 vaccines in routine use globally by 2030, costing an estimated US$20 billion a year to apply, compared with the current cost of US$1–2 billion and contributions from recipient countries as well as donors are likely to be required to meet the financial burden (Greenwood, et al., 2011).

To weigh against the high economic costs of vaccine development and delivery, immunisation programmes have resulted in some remarkable public health achievements. In addition to averting many tens of millions of cases of morbidity and premature mortality from common infections worldwide, these achievements have included the global eradication of smallpox, the substantial global retreat of poliomyelitis and, in some countries, the sustained interruption of indigenous measles virus transmission. As described in Section 4.5, the US measles elimination drive of the 1990s has demonstrated that indigenous measles transmission can be interrupted in a large and diverse country with a routine two-dose vaccination strategy, thereby providing support for the feasibility of global measles eradication (Orenstein, et al., 2004). It is to the global eradication of diseases that we now turn.

Appendix 4.1: Vaccine Developments

In this Appendix, we survey the development of vaccines which, today, form a central part of the routine childhood immunisation schedules of many countries against common infectious diseases. Our review draws, in part, on Parish (1968) and Plotkin, et al. (2008).

Diphtheria, Tetanus and Pertussis

Diphtheria. The possibility of protecting against diphtheria by inoculation of modified toxin to stimulate the production of antitoxin has been known since the late nineteenth century. In 1890, Emil von Behring and S. Kitasato demonstrated that guinea pigs, when immunised with heat-treated diphtheria toxin, produced antitoxin that prevented the harmful effects of C. diphtheriae. In 1907, von Behring established that a suitably balanced preparation of diphtheria toxin and antitoxin could produce safe and lasting immunity to diphtheria in humans while, by the early 1920s, Gaston Ramon at the Pasteur Institute, Paris, had developed a method of diphtheria toxoid production for medical use. The efficacy of large-scale diphtheria immunisation was clearly demonstrated in towns and cities of Canada and the USA in the 1920s and 1930s.

Tetanus. In 1890, von Behring and Kitasato – suspecting tetanus to be the result of a toxin released by the tetanus bacterium – published evidence that would form the basis of tetanus serotherapy. Tetanus antitoxin was found to be a valuable prophylactic for human tetanus and was in use for the treatment of wounds at the start of the twentieth century. Building on the knowledge acquired from studies of diphtheria, Ramon and Zoeller were the first to immunise a human being with a vaccine containing tetanus toxoid. British, French and US troops were vaccinated against tetanus with outstanding success in the Second World War, while the early post-war years marked the introduction of tetanus immunisation to the civil population of many countries.

Pertussis. In 1906, Belgian scientists Jules Bordet and Octave Gengou isolated the bacterium Bordetella pertussis, the causative agent of pertussis (whooping cough), which they had first observed in 1900. Bordet and Gengou prepared a pertussis vaccine from killed whole-cell B. pertussis preparations in 1912. In 1925, the Danish physician, Thorvald Madsen, tested his pertussis vaccine in children in the Faroe Islands. The vaccine seemed to provide protection against disease. However, another Madsen study, published in 1933, reported that two children died from what may have been reactions to the vaccine. Active work on pertussis vaccines was undertaken in the United States in the period 1926–48, notably by Louis Sauer and Pearl Kendrick, although controversy surrounded their claims of success. In Britain, Medical Research Council (MRC) investigations of the value of pertussis vaccines had begun in 1942 and, by the end of 1952, some two-thirds of local health authorities in England and Wales had received Ministry of Health approval for the establishment of prophylactic schemes.

Combined vaccines. Combined diphtheria–tetanus (DT) and diphtheria–tetanus–pertussis (DTP) vaccines were first licensed in the United States in the late 1940s (Table 4.2). The triple vaccine was adopted in most European countries in the following decade while, in 1974, it was recommended for use by the World Health Organization’s Expanded Programme on Immunization (WHO-EPI). During the 1990s, a combined diphtheria–tetanus–pertussis vaccine that used an acellular pertussis vaccine (DTaP), associated with fewer side effects, replaced DTP as the vaccine of choice in the routine childhood immunisation schedules of a number of countries.

Poliomyelitis

Reviews of the history and development of poliovirus vaccines are provided by Parish (1968), Paul (1971), Melnick (1978, 1997) and Salk and Salk (1984). The feasibility of a poliovirus vaccine was first demonstrated in 1934 by Maurice Brodie and John Kolmer. Their independent studies revealed that the immunisation of monkeys with formalin-inactivated (Brodie) and attenuated live (Kolmer) poliovirus produced a potent immune response to the virus. Although further investigations indicated that the resulting vaccines could stimulate antibody production in human beings, both were quickly withdrawn when paralytic disease began to appear in trial vaccinees. The major breakthrough came in 1955 when the success of trials of Jonas Salk’s inactivated poliovirus vaccine (IPV) were announced in the United States. Following the temporary suspension of IPV as a consequence of the Cutter incident (Section 4.6), mass immunisation with the inactivated vaccine recommenced in the United States and continued until the early 1960s when Albert B. Sabin’s live attenuated oral poliovirus vaccine (OPV) was licensed and adopted as the vaccine of choice (Table 4.2). OPV was subsequently adopted by the WHO-EPI and, since 1988, has formed a central plank of the WHO’s Global Polio Eradication Initiative.

Measles, Mumps and Rubella

Measles. The use of human convalescent serum to confer passive immunity against measles was first demonstrated by the Italian, Francesco Cenci, in 1901. In the United States, McKhann and Chu (1933), recommended the use of placental extract (human immune globulin) in place of serum as a reliable source of antibodies against measles. By 1944, Cohen and colleagues at Harvard had developed a human immune serum globulin, the gamma globulin fraction of the appropriate convalescent serum, taken from venous blood placentae. Gamma globulin replaced other products in the passive protection of measles until, in 1954, John Enders and Thomas Peebles at Harvard grew the measles virus in tissue culture. The first measles vaccine was tested in 1958 by a colleague of Peebles, Sam Katz, on children in a school near Boston; the development of symptoms of measles in the test cohort indicated that further attenuation of the live virus was required. The efficacy of a further attenuated vaccine (using the Edmonston-B strain of measles virus) was demonstrated by Enders and colleagues in 1961 and a vaccine using the Edmonston-B measles virus strain was licensed in the United States in 1963. In 1968, a more attenuated measles vaccine (Attenuvax), developed by Maurice Hilleman (Figure 4.2) and which did not require an injection of gamma globulin antibodies to reduce reactions, was licensed for use in the United States (Table 4.2).

Mumps. During the Second World War, Enders worked on a project concerned with active and passive immunisation against mumps in man and, by the 1950s, attenuated live and killed mumps vaccines had been developed and were being implemented with success in some countries. The major breakthrough, however, came in March 1963 when Maurice Hilleman isolated mumps virus from his daughter during her illness. Hilleman attenuated the virus by passing it through chicken eggs and chick cells several times. In 1965, Hilleman and colleagues began to test their experimental mumps vaccine on children in the Philadelphia area. The US Food and Drug Administration licensed Hilleman’s mumps vaccine (MumpsVax) in March 1967 (Table 4.2).

Rubella. In 1969, Hilleman modified a rubella vaccine virus that had been obtained from from Paul Parkman and Harry Meyer, scientists at the Division of Biologics Standards. The vaccine entered commercial use in the United States in 1969 (Table 4.2). A decade later, in 1979, the original rubella vaccine was replaced in the United States by Stanley A. Plotkin’s newly licensed RA27/3 vaccine, which had been used in Europe for years and which provided superior protection to that of the initial strain.

Combined vaccines. Initial tests on a triple measles–mumps–rubella (MMR) vaccine, undertaken in the United States in 1968, demonstrated that adverse reactions were no greater than seen in single vaccines. Merck’s combined MMR vaccine was licensed in the USA in 1971 (Table 4.2), with research indicating that the combined vaccine, properly administered, induced immunity to measles in 96 percent of vaccinated children; to mumps in 95 percent; and to rubella in 94 percent. Combined measles–mumps, measles–rubella and mumps–rubella vaccines were also developed for use in specific target groups at this time (Hilleman, 1992).

Tuberculosis

In 1904, Albert Calmette and Jean-Marie Camille Guérin began to attenuate Mycobacterium bovis to the point that it proved non-fatal to guinea pigs. Almost two decades later, in 1921, Calmette and Guérin began the first human tests of their attenuated vaccine preparation that was designated BCG (Bacillus Calmette-Guérin) and, in 1928, the Health Committee of the League of Nations adopted BCG as the tuberculosis vaccine of choice for preventative inoculation. The vaccine was widely used in France, central Europe and the Balkans after its introduction, although it was little employed in the United States until after 1940. The generalised international use of BCG vaccination began after the Second World War when it was administered as part of the International Tuberculosis Campaign of 1948–51, first in Europe and then in other parts of the world.

Other Diseases

Haemophilus influenzae type b (Hib) disease. The bacterium Haemophilus influenzae was first isolated in 1892 by the German physician Richard Pfeiffer, believing that he had identified the causative agent of influenza. The link between H. influenzae and meningitis was established in the United States by Margaret Pittman in 1931; Pittman found that strains of the bacterium that caused meningitis were characterised by a specific polysaccharide. These strains were referred to as H. influenzae type b (Hib). Half a century later, in 1985, the first polysaccharide Hib vaccines were licensed in the United States (Table 4.2). The polysaccharide vaccines were subsequently replaced in the US and elsewhere by conjugate Hib vaccines, including polyvalent preparations that also offer protection to diphtheria, tetanus and pertussis and to other diseases.

Hepatitis B. The identification of the hepatitis B virus (HBV) surface protein (‘Australia antigen’) by Baruch Blumberg in 1965 provided an important stimulus for the development of a hepatitis B vaccine. Maurice Hilleman transformed the Australia antigen into an effective vaccine (Hepatavax B) that was licensed in the United States in 1981. Heptavax was demonstrably effective in preventing hepatitis B although, because of concerns over HIV infection, it was superseded by a recombinant vaccine (Recombivax HB) that did not use human serum in 1986 (Table 4.2).

Meningococcal disease. Polysaccharide vaccines to protect against meningococcal disease were first licensed in the United States in the 1970s (Table 4.2). In the United Kingdom, clinical trials demonstrated that meningococcal C conjugate (MCC) vaccines were immunogenic and safe in all age groups and the first MCC vaccine was licensed in the UK in 1999. In subsequent years, quadrivalent conjugate vaccines to protect against serotypes A, C, Y and W-135 have been developed and introduced into the routine childhood immunisation schedule of some countries.

Pneumococcal disease. Although a killed whole-cell pneumococcal vaccine had been trialled by Almroth Wright in South African gold miners in the early twentieth century, the results of the trials were inconclusive and the vaccine was abandoned. The idea of a vaccine was taken up again by Robert Austrian in the 1960s. Having identified many different serotypes of the pneumococcus, Austrian reported in 1976 that a pneumococcal vaccine had been developed that had proved safe and effective in South African trials. Austrian’s polysaccharide vaccine, protective against 14 types of pneumococcal bacteria, was licensed in the United States in 1977. The polysaccharide vaccine, however, did not consistently induce immunity in young children (aged < 2 years) and, in subsequent years, safe and effective conjugate vaccines have been developed and released onto the market.

Rotavirus gastroenteritis. The first vaccine for rotavirus (RotaShield) was licensed and recommended for routine childhood immunisation in the USA in 1998. Following the withdrawal of RotaShield in 1999 on account of its association with potentially fatal intestinal complications, a new vaccine (RotaTeq) was developed and recommended for inclusion in the routine infant immunisation schedule of the United States in 2006.