8.3 Immunization 706

8.3 Immunization 706

ESSENTIALS Immunization is one of the most successful medical interventions ever developed: it prevents infectious diseases worldwide. Mechanism of effect—​the basis for the success of immunization is that the human immune system is able to respond to vaccines by pro- ducing pathogen-​specific antibody and memory cells (both B and T cells) which protect the body should the pathogen be encountered. Clinical practicalities—​most currently licensed vaccines contain live or killed bacterial or viral constituents, bacterial polysaccharides, or bacterial toxoids, while new types of vaccines are being developed that contain DNA. Most vaccines are delivered directly into skin or muscle via needles, or they are administered orally. New edible vac- cines and vaccines delivered via the skin without the use of needles are being developed. Who should be immunized?—​vaccines can be used in a targeted way (i.e. only for those at high risk), or they can be recommended for mass immunization of whole populations. The latter approach may eventually lead to complete eradication of an infectious disease, as was the case with smallpox: polio eradication is the next global chal- lenge. Vaccines that can interrupt the transmission of a pathogen between individuals are able to provide indirect protection, with the benefit of vaccination extending beyond the vaccinated population (e.g. infant immunization with pneumococcal vaccine has reduced the burden of disease in adults). Global perspective—​the Expanded Program on Immunization, set up by the World Health Organization to define which vaccines should be delivered in resource poor countries, has done much to increase coverage of vaccination among infants most at risk of infec- tious diseases. The evaluation of immunization programmes includes measurement of vaccine coverage, continuing surveillance for vaccine-​ preventable infections, seroprevalence studies to assess population immunity, and systems for monitoring and reporting adverse events. Introduction Infectious diseases remain a major cause of mortality and mor- bidity worldwide. The prevention of certain infectious diseases by effective immunization programmes is one of the major triumphs of 20th-​century medicine. Most of this was achieved in the final third of that century, during which rapid strides in the understanding of the biology and pathogenicity of infectious agents or their compo- nents, and improved techniques for their purification, led to the de- velopment of safe and effective vaccines. The greatest triumph in the field of immunization was the eradication of smallpox. In 1959 the World Health Organization (WHO) declared its intention to eradi- cate smallpox, and in 1966 began to allocate sufficient resources to accomplish this ambitious goal. Thirteen years later, in 1979, the global eradication of smallpox was officially declared. Effective vac- cines can eliminate infectious diseases, but to do this they must be implemented and used appropriately. Of the more than 12 mil- lion children under the age of 5 years who die annually, 2.4 million die of diseases that could be prevented by vaccines already avail- able through the WHO’s Expanded Programme on Immunization. While rapid advances in vaccine science have introduced new tech- niques such as DNA vaccines, delivering vaccines to those most at risk must remain a priority. Immunology of active immunization Both non​specific (innate) and specific (adaptive or acquired) im- mune systems are responsible for protecting humans against infec- tious diseases. The ability of the adaptive immune system to refine its antigen-​recognition domains and establish immunological memory is the basis of successful active immunization. The antigen-​specific component of the immune system contains both cellular and hu- moral elements (secreted antibody), whose relative importance dif- fers depending on the nature of the infecting organism. Cellular responses are induced when antigen-​presenting cells, such as dendritic cells, present antigens to T cells. T cells do not respond to soluble, unmodified antigens, and only recognize pep- tide antigens in association with major histocompatability com- plex (MHC) molecules. Two major forms of MHC molecules exist. Most nucleated cells produce MHC class I molecules, which stimulate a subset of T cells that produce the CD8 differentiation antigen. These T cells recognize and lyse infected target cells, hence their designation as cytotoxic T lymphocytes. By contrast, MHC class II molecules are produced by cells that participate in the immune response, and are recognized via a subset of T cells 8.3 Immunization David Goldblatt and Mary Ramsay

8.3  Immunization 707 producing the CD4 differentiation antigen. A major role of such T cells is to augment the immune response, and so they are known as T helper cells. Several subsets of T helper cells have been de- scribed: T helper 1 cells are involved in cytotoxic and delayed-​type hypersensitivity responses, T helper 2 cells support antibody pro- duction, follicular helper T cells provide help to B cells enabling them to develop into antibody-​secreting plasma cells, while Th17 cells are important for protection against bacteria and fungi at mucosal surfaces. Immunoglobulin receptors on the surface of B cells are able to recognize soluble antigens, and so initiate the process of B-​cell activation and differentiation. During differentiation, naive B cells become antibody-​secreting plasma cells. In addition, B cells endocytose antigen bound to their surface immunoglobulins, and re-​express it in the form of small peptides on the surface of the B cell in the context of MHC class II molecules. Thus, B cells act as antigen-​presenting cells and recruit T-​cell help. The signals and sol- uble factors that result from such T-​cell help drive the B-​cell process of affinity maturation and memory formation. This takes place in the germinal centres of lymph nodes, where there is intimate contact between B cells, T cells, and dendritic cells. It is here that memory B cells are formed and then migrate to the bone marrow, spleen, and the submucosa of the respiratory tract and gut. On re-​encountering the antigen, memory B cells undergo rapid activation and differenti- ation into plasma cells, and secrete large amounts of switched, high-​ affinity antibody. Thus, the ideal vaccine antigen will lead to the activation, replica- tion, and differentiation of T and B lymphocytes. Ideally the antigen will persist in lymphoid tissue, conformationally intact, to allow the continuing production of cells that secrete high-​affinity antibody, and the generation of memory cells. Vaccine antigens The ideal vaccine antigen is safe, with minimal side effects, pro- motes effective resistance to the disease (although it does not neces- sarily prevent infection), and promotes lifelong immunity. It needs to be stable and remain potent during storage and shipping, and also has to be affordable to allow widespread use. Most currently li- censed vaccines contain live or killed bacterial or viral constituents, bacterial polysaccharides, or bacterial toxoids (Table 8.3.1). Live vaccines are ideal for certain diseases, as replication in the body mimics natural infection, thereby inducing appropriate and site-​specific immunity. Live vaccines must be attenuated to remove the danger of clinical disease, but retain the beneficial effects of inducing immunity. Some live vaccines may be spread from person to person, and thus enhance herd immunity, although such spread may endanger immunocompromised individuals, in whom live vac- cines should be avoided. Live vaccines are inherently less stable than killed vaccines, and the possibility of reversion of vaccine virus to the wild type exists (as in polio). Killed vaccines do not carry the risk Table 8.3.1  Currently licensed vaccines for use in humans Vaccine type Live vaccines Killed/​subunit vaccines Viral Rubella Poliomyelitis (Salk) Measles Influenza Poliomyelitis (Sabin) Rabies (human diploid cell) Yellow fever Hepatitis A Mumps Hepatitis B Varicella zoster (chicken pox) Japanese encephalitis Rotavirus Human papillomavirus Herpes zoster (shingles) Tick-​borne encephalitis Dengue yellow fever vaccine Hepatitis E Bacterial Bacillus Calmette–​Guérin Cholera Typhoid Typhoid Neisseria meningitidis group B Cholera Pertussis Borrelia burgdorferi Anthrax Plague Bacterial polysaccharides Haemophilus influenzae type b Neisseria meningitidis group A, C, Y, W135 Streptococcus pneumoniae Rickettsial Typhus Bacterial toxoid Diphtheria Tetanus Parasitic Malaria

708 SECTION 8  Infectious diseases associated with person-​to-​person spread, and are inherently more stable, but often require two or three doses to induce optimal im- munity, especially when used in the first year of life. New developments in vaccine antigens Developments in molecular biology have begun to revolutionize the field of vaccine science, and provide a glimpse of the future, when the traditional reliance on live attenuated viral vaccines or purified bac- terial or viral products as vaccine antigens may be reduced. The first licensed vaccine to contain recombinant genetic material was the hepatitis B vaccine. Despite the licensing of highly effective plasma-​ derived hepatitis B vaccines in the early 1980s, fears about safety, and their high cost, led to the search for other hepatitis B vaccines. Several vaccine manufacturers used recombinant DNA technology to express hepatitis B surface antigen in other organisms, which led to the development of new vaccines. DNA itself has also attracted interest as a vaccine antigen. The po- tential of this approach was discovered by chance in 1989 during a gene therapy experiment, when it was shown that a gene inserted directly into a mammalian cell could induce the cell to manufacture the protein encoded by that gene. In early experiments, DNA was in- jected directly into muscle, and the resulting immune response was measured. DNA vaccines can induce protective immunity to a variety of pathogens in animals, but data in humans are limited. As DNA has the theoretical potential to be incorporated into the host’s genetic makeup and subvert the genetic working of cells, safety concerns have delayed studies in humans. Phase I studies, however, have as- sessed DNA vaccines designed to protect against hepatitis B, herpes simplex type 1 and 2, HIV, influenza, and malaria. So far clinical trials have proved disappointing, either because the level of the re- sponse was inadequate or because excessive doses of DNA were re- quired to achieve an adequate response. This poor immunogenicity of DNA vaccines remains a major hurdle. Prime-​boost strategies where the immune system is primed with a vector coding for one antigen and then subsequently boosted with a different vector or the antigen itself has been the one area of promise in this field and has been applied to malaria, HIV, and new tuberculosis vaccines. The abundant information now available about the genomic makeup of pathogens has ushered in a new era that has been termed ‘reverse vaccinology’. Using information from the pathogen genome, sequences coding for likely protective antigens have been cloned into expression systems, expressed and screened as vaccine antigens using animal models. A related but alternative technique involves highly representative small-​fragment genomic libraries that are expressed to display frame-​selected epitope-​size peptides on a bacterial cell surface. These are then screened with disease-​relevant high-​titre sera and the candidate antigens recognized are assessed further for their potential as vaccine antigens. This approach has been described for several bacteria including Neisseria meningitidis, Staphylococcus aureus, and epidermidis; Streptococcus pyogenes, aga- lactiae, and pneumoniae; Enterococcus faecalis; Helicobacter pylori; Chlamydia pneumoniae; the enterotoxigenic Escherichia coli; and Campylobacter jejuni. The first vaccine to be developed using this approach (4C-​MenB, Bexsero® GSK Biologicals) was licensed in the European union in 2013. The vaccine is designed to offer broad coverage against inva- sive strains of serogroup B meningococcal infection. This vaccine contains three recombinant proteins (Neisserial adhesin A (NadA), factor H binding protein (FHbp), and Neisserial heparin binding antigen), identified using reverse vaccinology; the fourth compo- nent is from an outer membrane vesicle vaccine that was used suc- cessfully in New Zealand. The vaccine has been used on a wide scale in response to an outbreak in Quebec, and in a university outbreak in the United States. In September 2015, the United Kingdom be- came the first country to incorporate this vaccine into its routine infant programme. A second vaccine against serogroup B menin- gococcal infection (MenB-​FHbp Trumemba, Pfizer) was approved for use by the US Food and Drug Administration (FDA) in October 2014. MenB-​FHbp consists of two recombinant FHbp antigens, one from each subfamily (A and B), and provides another option for protecting older children (aged 10 years or above) from this serious disease. Despite these new technologies, vaccines for some pathogens are proving difficult to develop. Vaccines for HIV remain a major health priority, but phase III clinical trials to date have proved disappointing. The RV144 HIV vaccine trial is the only phase III vaccine trial that has shown a modest protection (31%) against HIV infection. It was conducted in Thailand where more than 16 000 participants re- ceived four priming injections of a recombinant canarypox vector vaccine plus two booster injections of a recombinant glycoprotein 120 subunit vaccine. Despite the relatively modest effect of the vac- cine, the large study size will permit the evaluation of correlates of protection which are vital for the ongoing effort to find a safe and effective vaccine. Improved vaccines for tuberculosis are a priority as the Bacillus Calmette–​Guérin (BCG) vaccine provides imperfect protection. Several recombinant BCG constructs have entered clinical trials and several new subunit vaccines, formulated as adjuvanted or viral vectored vaccines and designed to be used with BCG in a ‘prime-​ boost’ approach are currently in clinical trials. The recent unpre- cedented epidemic of Ebola virus disease epidemic in West Africa in 2014–​2015 acted as a stimulus for the first large scale use of a viral vectored vaccine. A live attenuated recombinant vesicular sto- matitis virus (VSV), where the G-​protein associated with viru- lence was replaced by the Ebola glycoprotein from the Zaire strain (rVSV–​EBOV) was used in phase III clinical trials in both Guinea and Sierra Leone. Ring vaccination of contacts with a single dose of rVSV–​EBOV was shown to provide 100% efficacy when given im- mediately in a cluster, when compared to those clusters when vac- cination was delayed. Phase III trials of a second vaccine (cAd3-​EBO Z), using a replication-​deficient adenovirus chimpanzee serotype 3 (cAd3) vector expressing Ebola glycoprotein from the Zaire strain, were also planned in Liberia, but progress has been slow due to small numbers of cases of Ebola virus disease. To provide the potential for longer-​term protection, the prime-​boost strategy, using two doses of vaccine each delivered on a different viral vector, are now underway. New developments in vaccine delivery Research into different routes of vaccine delivery has been driven by the limitations of the parenteral route. These include the difficulty associated with the use of live viral vaccines in the first 6–​9 months

8.3  Immunization 709 of life (because of the neutralizing effect of passively transferred ma- ternal antibody) and the difficulty and expense of delivering mass immunization by injection. Mucosal delivery of vaccine via the intranasal route has been studied for several antigens, including measles, influenza, rubella, varicella, and Streptococcus pneumoniae. The induction of local immunity for pathogens that either enter the body via the nasopharynx (measles, influenza) or are commonly carried in the nasopharynx (S. pneumoniae) is attractive. Edible vaccines are attracting increasing attention, providing as they do both a means of antigen production and delivery. Studies in animals, and phase I studies in humans, have demonstrated their ­potential. Mice fed with potatoes expressing a non​toxic fragment of the cholera toxin developed mucosal antibodies to the toxin, which reduced diarrhoea on challenge with whole cholera toxin. Humans fed raw potatoes expressing the B subunit of enterotoxi- genic Escherichia coli also showed mucosal immune responses and an increase in neutralizing antibody levels. There are some problems with stability, but edible vaccines are a potentially simple and con- venient method of vaccine delivery on a wide scale. The requirement for increased immunogenicity of existing vac- cines has driven the search for better adjuvants. Until recently the only adjuvants in widespread use have been aluminium salts. New, safe adjuvants with acceptable safety profiles are finally appearing in vaccines and include oil in water emulsions such as ASO3 used in influenza vaccines, and a combination of aluminium hydroxide and monophosphoryl lipid A (ASO4), used for human papilloma virus vaccine and hepatitis B vaccine. Experience with H1N1 influenza vaccines, containing another oil in water adjuvant (MF-​59), have demonstrated good immune response to a novel strain of influenza with only a single dose, thus enabling vaccine to provide protection earlier than expected in the recent pandemic. The aim of immunization programmes Once a vaccine has been developed and shown to be effective it can be used in different ways. Many vaccines are used selectively in groups of the population who are at increased risk of infection (e.g. because of occupation or travel) or of severe consequences of the disease (e.g. because of an underlying medical condition). Other vaccines are employed for mass immunization targeting the whole population. Mass immunization can eradicate, eliminate, or control an infectious disease. Eradication, the state where a disease and its causal agent have been removed from the natural environment, has been achieved only for smallpox. Once eradication has been certi- fied, mass immunization programmes can cease, and resources can be transferred to other programmes. The next target for the WHO is the global eradication of polio- myelitis. Characteristics that favour eradication are the absence of an animal host, the absence of a carrier state, and lifelong protec- tion given by vaccination. The polio eradication campaign has in- volved the use of National Immunization Days (NIDs), on which live attenuated polio vaccine is delivered to a high proportion of the childhood population on a single day. Millions of children have been immunized with trivalent oral polio vaccine (against types 1, 2, and 3) during NIDs. This had led to the successful interrup- tion of poliovirus transmission in many previously endemic coun- tries and no cases of type 2 poliovirus (WPV2) have been detected since 1999. In 2015, WPV2 was declared eradicated, but, as eradica- tion of wild virus nears, concern about the persistent circulation of vaccine-​derived polioviruses (cVDPVs) have become greater. July 2015 marked an important step on the road to a world without polio. No cases of wild poliovirus infection had occurred in Nigeria for a whole year, and infection remains endemic in only two countries—​ Afghanistan and Pakistan. During 2015, however, more countries were affected by cVDPVs than by the wild polio viruses. Therefore, as part of the global endgame, a switch from the use of trivalent oral polio vaccine to the bivalent version, without the type 2 component, is planned from April 2016. For some infections, eradication by immunization is not possible. A good example is tetanus, where the agent is distributed widely in the environment. For these programmes the aim is to control in- fection to the point where it no longer constitutes a public health burden. To maintain control, immunization must be continued indefinitely. For diseases that are transmitted from person to person, a good immunization programme provides protection by conferring both individual and herd immunity. For many vaccines, herd immunity can be achieved by vaccinating a high proportion of the childhood population; older individuals are generally immune as a result of previous natural infection. If such a situation can be sustained, transmission of the infection may be interrupted, and elimination or eradication becomes possible. If vaccine coverage or efficacy is sub- optimal, however, then, in the absence of natural transmission, the number of susceptible people will gradually increase. Eventually, the proportion of susceptible people (those who did not receive vaccine or who failed to respond to it) may reach a level sufficient to support an epidemic. Although the size of these epidemics may be small by prevaccine standards, the average age of those infected will be higher than in the prevaccine era. For infections that have more severe con- sequences in older individuals the morbidity associated with such outbreaks can be substantial. A tragic example of this was observed in Greece, where mass vaccination against rubella in childhood was recommended from 1975. Implementation was poor, however, and during the 1980s coverage was below 50%. The low level of coverage was sufficient to interrupt transmission for several years, but by the time rubella infection recurred in 1993, a high proportion of preg- nant women were susceptible to rubella and an epidemic of con- genital rubella syndrome occurred. Other potential negative consequences of achieving high vaccine coverage, and therefore high herd immunity, have been described. One negative impact may be that pressure is created on an organism to mutate, or that other strains may expand to fill an ecological niche left, for example, by eradicating nasopharyngeal carriage. The introduction of a 7-​valent pneumococcal conjugate vaccine into the routine infant immunization programme of the United States of America, and the associated surveillance for invasive pneumo- coccal disease, has revealed not only the direct impact of the vaccine in reducing disease in vaccinated children, but also a huge indirect effect, which has resulted in the reduction of invasive pneumococcal disease in unvaccinated adults. A similar experience, however, has been followed by an increase in serotypes not covered by the vaccine in several countries. Vaccines with higher valencies (covering 10 or 13 serotypes) are now being employed; long-​term surveillance to monitor whether these too lead to replacement is essential. Another negative impact of the introduction of vaccination may be disruption

710 SECTION 8  Infectious diseases of asymptomatic transmission and reduction in natural boosting of immunity. This can result in protection from vaccine waning earlier than expected, and therefore in resurgences in disease in older indi- viduals. This may partially explain some of the recent outbreaks of mumps described in several countries with high vaccine coverage. Although it is clear that morbidity associated with mumps in vac- cinated individuals is substantially reduced, waning immunity may prevent the long-​term elimination of mumps infection. Delivery of immunization programmes In 1974 the WHO launched the Expanded Programme on Immuni­ zation, in recognition of the major contribution of vaccines to public health. At the start of the programme fewer than 5% of the world’s infants were immunized against the six target diseases: diphtheria, tetanus, whooping cough, polio, measles, and tuberculosis. Between 1990 and 1997, around 80% of the 130 million children born each year were immunized by their first birthday, preventing around 3 million deaths each year. Each year, more than 500 million immun- ization contacts occur with children, and these have provided an op- portunity for the delivery of other primary healthcare interventions. During the 1990s the Expanded Programme on Immunization added immunization against yellow fever and hepatitis B to its target diseases. As a major barrier to using new vaccines is access to sus- tainable funding, the introduction of the new vaccines has been slower, particularly in the poorest countries in greatest need. In 2001, an aid consortium known as the Global Alliance for Vaccines and Immunization has been supporting vaccination programmes in around 75 of the poorest countries. This model has helped to reduce the cost and the risk of producing vaccines for developing coun- tries, by supporting long-​term contracts at high volumes and low unit costs. In 2012, the World Health Assembly endorsed the Global Vaccine Action Plan which aims to prevent millions of deaths by 2020 through more equitable access to existing vaccines for people in all communities. The plan involves four main goals: to strengthen routine immunization to meet vaccination coverage targets; to ac- celerate control of vaccine-​preventable diseases with polio eradica- tion as the first milestone; to introduce new and improved vaccines; and to spur research and development for the next generation of vaccines and technologies. Six strategic objectives of the Global Vaccine Action
Plan 2011–​2020 • All countries commit to immunization as a priority. • Individuals and communities understand the value of vaccines and demand immunization as both their right and responsibility. • The benefits of immunization are equitably extended to all people. • Strong immunization systems are an integral part of a well-​ functioning health system. • Immunization programmes have sustainable access to predictable funding, quality supply, and innovative technologies. • Country, regional, and global research and development innov- ations maximize the benefits of immunization. The plan recognizes that, for mass immunization to achieve its aims, high and uniform coverage of immunization must be reached and sustained. The level of coverage of immunization is associated with a variety of factors, including the sociodemographic characteristics of the population, the organization of health services, knowledge among health professionals, and parental attitudes. Sociodemographic factors that may influence vaccine coverage include deprivation, maternal education, and family size. Centrally coordinated health services with few barriers to access, and standard record systems with facilities for call and recall are likely to achieve higher vaccine coverage. Health professionals with accurate know- ledge of the indications and true contraindications to immunization are important. Excessive lists of contraindications for diphtheria–​ tetanus–​pertussis immunization in the newly independent states of the former Soviet Union contributed to a massive resurgence of diphtheria in the early 1990s. The number of cases rose from 2000 in 1990 to over 47 000 in 1994; 2500 deaths from diphtheria occurred between 1990 and 1995. Whether or not parents decide to have their children vaccinated depends on their perceptions of the severity of the disease and of the safety and effectiveness of the vaccine. Knowledge of parental per- ceptions can be used successfully to target health promotion cam- paigns. When coverage is high, the incidence of vaccine-​preventable disease declines, and parental perception of the severity of that dis- ease may decrease. In this situation, concerns about the safety of the vaccine become paramount and can lead to a decline in vaccine coverage. Such a situation arose in the United Kingdom in the early 1970s, when concern about the safety of pertussis vaccine led to a fall in coverage. This resulted in resurgence of the disease, with con- sequent mortality and morbidity (Fig. 8.3.1). Over the next decade vaccine coverage improved again, and the incidence of the disease fell to the lowest levels ever. In 2003–​2004, concern about the safety of the polio vaccine led to the suspension of the programme in northern Nigeria. This led to an outbreak of polio in west and central Africa and the re- introduction of poliovirus into 22 previously polio-​free countries. By 2005, after massive efforts from the international community, successful campaigns were launched to stop these outbreaks and transmission was contained in all but six of these countries. In 2008, a further polio outbreak occurred in Nigeria, leading to persistent importations into neighbouring countries and re-​ established transmission in Angola, Chad, the eastern part of 200000 180000 160000 140000 120000 100000 80000 60000 40000 20000 Notifications 0 80 40 0 – 40 Coverage 1940 1943 1946 1949 1952 1955 1958 1961 1964 1967 1970 1973 1976 1979 1982 1985 1988 1991 1994 1997 Notifications Vaccine coverage (%) *Provisional Year Fig. 8.3.1  Whooping cough cases and vaccine coverage in England and Wales between 1940 and 1998.

8.3  Immunization 711 Democratic Republic of Congo, and southern Sudan. This experi- ence illustrates the major global implications of failure to sustain confidence in vaccination. Evaluation of immunization programmes Evaluation of an immunization programme may include the meas- urement of vaccine coverage, surveillance of disease incidence, as- sessment of prevalence of immunity, and the monitoring of adverse events. Vaccine coverage Timely measurement is important for monitoring trends in vaccine coverage and identifying pockets of low coverage. Low coverage may be apparent before any increase in disease incidence is observed. Since the late 1970s, three outbreaks of poliomyelitis have been ob- served among groups in the Netherlands with religious objections to immunization. Despite national coverage of 96% for the measles, mumps, and rubella (MMR) vaccine, the same group has been the focus of a large epidemic of measles. Between April and December 1999, 1750 cases of measles occurred in the Netherlands, compared with only 9 in the whole of 1998. Disease surveillance Once an immunization programme has been implemented, dis- ease incidence data can be used to monitor the effectiveness of the strategy. For example, the dramatic decline in the incidence of invasive Haemophilus influenzae infection described in both the Netherlands and the United Kingdom can be used to demonstrate the impact of conjugate vaccination. The age distribution of infec- tion may change, as children above or below the target age form an increasing proportion of those infected. Various epidemiological methods, including case–​control studies, cohort studies, and the screening method can be used to estimate the efficacy of the vac- cine in the field. The impact of vaccines should be monitored in age groups other than those targeted by vaccination, to determine the effect of herd immunity. Neisseria meningitidis group C (Men C) polysaccharide-​conjugate vaccine was introduced into the United Kingdom in 1999 and by 2002 all under the age of 25 years in the population had been offered the vaccine. The effect of invasive Men C disease reduction was, however, seen in all ages, both those dir- ectly immunized and those protected by reduced transmission of the bacterium from the nasopharynx in vaccinated individuals to the rest of the population (Fig. 8.3.2). Seroprevalence studies Seroprevalence studies are used to assess population immunity to infection. Such immunity results either from immunization or from natural infection. This can detect groups that include a high proportion of susceptible individuals, who may be the focus of future outbreaks. In 1991, seroprevalence studies in the United Kingdom identified that a large proportion of school-​age children was susceptible to measles, and therefore that an epidemic of mea- sles was likely. A large campaign was mounted in November 1994 to immunize children from 5 to 16 years of age. The number of cases of measles fell rapidly and remained at low levels over the next 5 years. Adverse events The monitoring of adverse events is important for maintaining public confidence in an immunization programme and for detecting rare events that could not be identified before licensing the vaccine. The detection of such events may lead to the withdrawal of certain vaccines. In August 1998, a quadrivalent vaccine using reassortant rhesus rotavirus strains was licensed for use in the United States of America and recommended for the mass immunization of infants. During prelicensing studies, five cases of intussusception had been reported in around 10 000 recipients, compared with only 1 in al- most 5000 controls; this difference was not statistically significant. During postlicensure surveillance, however, 15 cases were reported to the Vaccine Adverse Event Reporting System. On 22 October 1999, a review of scientific data concluded that there was an in- creased frequency of intussusception in the 1–​2 weeks after vac- cination, which led to withdrawal of the first licensed vaccine. New rotavirus vaccines that appear to be less likely to produce intussus- ception are now licensed. Adverse events may be linked to the ac- tive antigen or to other contents of the vaccine. Concerns in Finland about an observed excess of cases of narcolepsy occurring after the adjuvanted pandemic influenza vaccine suggest that the novel adju- vant MF-​59 may be a trigger. A live attenuated tetravalent chimeric vaccine designed to prevent Dengue infection (Dengvaxia®) was li- censed in 2016 and has been used for immunization of children in the Phillipines. Its use has been associated with more severe disease in vaccine recipients who have never been exposed to Dengue. The immunization campaign has been suspended while this association and safety data are evaluated further. FURTHER READING Bernier RH, Hinman AR (1988). Assessing vaccine efficacy in the field: further observations. Epidemiol Rev, 10, 212–​41. Centers for Disease Control and Prevention (2005). Direct and indirect effects of routine vaccination of children with 7-​valent pneumococcal 0 100 200 300 400 500 600 700 800 97/98 98/99 99/00 00/01 '01/02 '02/03 '03/04 '04/05 '05/06 '06/07 '07/08 '08/09 09/10 10/11 11/12 12/13 13/14 14/15 No of cases Year 20 + yrs Under 20 Fig. 8.3.2  Cases of invasive disease due to Neisseria meningitidis capsular group C infections England 1998/​1999–​2014/​15 epidemiological years (July to June). Data from Public Health England: https://​www.gov.uk/​government/​uploads/​ system/​uploads/​attachment_​data/​file/​470612/​Table_​8_​Invasive_​meningococcal_​C_​ infections_​lab_​reports_​_​England_​by_​age_​group_​_​_​epi_​year.pdf

712 SECTION 8  Infectious diseases conjugate vaccine on incidence of invasive pneumococcal disease—​ United States, 1998–​2003. MMWR Morb Mortal Wkly Rep, 54, 893–​7. Chen RT (1999). Vaccine risks: real, perceived and unknown. Vaccine, 17, S41–​6. Czerkinsky C, et al. (1999). Mucosal immunity and tolerance: rele- vance to vaccine development. Immunol Rev, 170, 197–​222. Henao-​Restrepo AM, et  al. (2015). Efficacy and effectiveness of an rVSV-​vectored vaccine expressing Ebola surface glycoprotein: in- terim results from the Guinea ring vaccination cluster-​randomised trial. Lancet, 386, 857–​66. Ladhani SN, et al. (2015). The introduction of the meningococcal B (MenB) vaccine (Bexsero(®)) into the national infant immunisation programme—​new challenges for public health. J Infect, 71, 611–​4. Lehtinen M, et  al. (2012). Overall efficacy of HPV-​16/​18 AS04-​ adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-​year end-​of-​study analysis of the randomised, double-​ blind PATRICIA trial. Lancet Oncol, 13, 89–​99. Leitner WW, Ying H, Restifo NP (1999). DNA and RNA-​based vac- cines: principles, progress and prospects. Vaccine, 18, 765–​77. Pilishvili T, et al. (2010). Active bacterial core surveillance/​emerging infections program network. sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis, 201, 32–​41. Rappuoli R, Black S, Lambert PH (2011). Vaccine discovery and trans- lation of new vaccine technology. Lancet, 378, 360–​8. Rerks-​Ngarm S, et  al. (2009). Vaccination with ALVAC and AIDSVAX to prevent HIV-​1 infection in Thailand. N Engl J Med, 361, 2209–​20. Tacket CO, et al. (1998). Immunogenicity in humans of a recom- binant bacterial antigen delivered in a transgenic potato. Nat Med, 4, 607–​9. Wichmann O, et al. (2017). Live-attenuated tetravalent dengue vaccines: The needs and challenges of post-licensure evaluation of vaccine safety and effectiveness. Vaccine, 35(42), 5535–42.