Global Public Health Impact of Vaccines in Children
- Peter McIntyrePeter McIntyreUniversity of Otago, Department of Women's and Children's Health, Dunedin School of Medicine
- and Tony WallsTony WallsUniversity of Otago Christchurch, Department of Paediatrics
From the first vaccine (cowpox, developed by Edward Jenner in 1796), more than 100 years elapsed before additional vaccines for broad population use (diphtheria toxoid, tetanus toxoid, and whole cell pertussis) became available between 1920 and 1940. Then followed inactivated polio vaccine in the 1950s, and live attenuated vaccines for measles, mumps, rubella, and polio in the 1960s. In 1979, global elimination of smallpox was formally certified, with the last human case occurring in Somalia, almost 200 years after Jenner administered cowpox vaccine to James Phipps.
In 2019, global elimination is tantalizingly close for maternal and neonatal tetanus and polio. Despite recent outbreaks, elimination has also been achieved at country and regional levels for measles and rubella and, if achieved globally, will offer, as it has for smallpox, large reductions in child mortality and morbidity and in health system costs. Short of elimination, it is important to define the public health impact of vaccines broadly and at the population level. These broader impacts include benefits to families flowing from prevention of long-term sequelae of infection in children, and to populations and health systems from reduced transmission of infection. Importantly, well-delivered vaccination programs will have a substantial impact by improving equality in health outcomes across populations. Broader impacts include reductions in syndromic disease beyond laboratory-proven infection (e.g., diarrhea and pneumonia), indirect reductions in disease in those not immunized (within and beyond age cohorts targeted by vaccine programs), and improvements in other health services driven by the infrastructure for vaccine delivery. Measurement of these broader impacts can be challenging and must also acknowledge the potential for trade-offs, such as replacement disease due to non-vaccine strains, as documented for pneumococcal infection.
The realization of the benefits of vaccines globally for all children began with the Expanded Program on Immunization (EPI) initiated by the World Health Organization (WHO) in 1974. The EPI focused on improving coverage of six already available but grossly underutilized vaccines—diphtheria–tetanus–pertussis (DTP), polio, measles, and Bacille Calmette–Guerin (BCG). Through the EPI, estimated global coverage for 3 doses of DTP increased from around 20% to over 85%. Subsequent to the EPI, the Global Alliance for Vaccines and Immunization (GAVI), the Global Immunization Vision and Strategy (GIVS), and, most recently, the Global Vaccine Action Plan (GVAP) have aimed to improve access to additional vaccines in the poorest countries. These include Haemophilus influenzae type b (Hib), hepatitis B, pneumococcal conjugate, rotavirus, and human papillomavirus (HPV) vaccines, all introduced in high-income countries from the 1990s. In this chapter, the scope and methodological issues in measuring public health impact are reviewed, and estimates of the global public health impact of individual vaccines in children summarized, concluding with potential future benefits to global child health from expanded maternal vaccination and vaccines under development.
Measuring the Public Health Impact of Vaccines
Some key concepts need to be considered in defining the scope of the public health or population-level impact of vaccines and its measurement, as follows: (a) efficacy versus effectiveness (Clemens et al., 1996),(b) direct versus indirect effects (often referred to as “herd immunity”) (Fine et al., 2011), (c) vaccine impact on disease syndromes such as diarrhea or pneumonia versus laboratory-confirmed infection (used to measure vaccine-preventable disease incidence) (Gessner et al., 2017), (d) the importance of disease severity, especially preventable long-term morbidity (often requiring periods of follow-up not achievable in vaccine trials), and (e) impacts on health systems and potentially the broader economy (Bärnighausen et al., 2014). Full assessment of overall public health impact must consider unwanted effects, such as local or systemic adverse reactions or offsetting of reductions in vaccine-type organisms by strains not included in the vaccine, and at global level, variations in impact in different settings.
Vaccine efficacy, as determined in vaccine trials, with randomization of receipt of vaccines and blinded outcome assessment, is the most rigorous measure of vaccine effect, typically required to achieve approval for human use by regulatory authorities. However, efficacy is limited to direct effects on trial participants, whereas when the vaccine is used in a whole population, “real-world” effectiveness is measured by overall reductions in disease, both directly (among vaccinated children in the eligible age group) and indirectly (including both unvaccinated children in the target group and persons of all ages) (Clemens et al., 1996). Population-wide use involves much larger numbers of vaccine recipients; thus, effects too rare to detect in a vaccine trial may become apparent. These may be both favorable, such as reductions in rarer subcategories of the disease [e.g. recurrent respiratory papillomatosis among infants born to mothers who have received human papillomavirus (HPV) vaccine; Novakovic et al., 2018] or unfavorable, such as intussusception among infants receiving rotavirus vaccine (Carlin et al., 2013). Some vaccines, such as measles, mumps, and rubella (MMR) vaccine, are effective only against infection with a specific virus, which is reliably detected by specific laboratory tests. Some vaccines have effects extending well beyond laboratory-confirmed infection, captured by measuring changes in cases presenting with clinical syndromes where laboratory tests are either not taken or are not positive (Saadatian-Elahi et al., 2016). Examples include all-cause pneumonia and pneumococcal conjugate and all-cause gastroenteritis and rotavirus vaccines (Cutts et al., 2005; Madhi et al., 2010).
The term “vaccine-preventable disease incidence” (VPDI) refers to the change in incidence of a disease or syndrome either within a clinical trial setting, whether individually randomized or more commonly randomized in larger population units, or at the population level post vaccine introduction. VPDI, because it necessarily incorporates measurement of disease burden in the population, allows comparison of vaccine impact in different epidemiological settings. An important example of the interplay between vaccine effectiveness and underlying disease burden is rotavirus vaccines, where although vaccine effectiveness is lower in high disease burden settings, such as sub-Saharan Africa (for reasons which are not completely understood), high baseline incidence and severity results in a greater overall reduction in VPDI than in settings with higher vaccine effectiveness but lower baseline disease burden (Gessner et al., 2017; Madhi et al., 2010). Similarly, studies of pneumococcal conjugate vaccines in the high disease burden setting of The Gambia showed the importance of measuring impact on clinically diagnosed pneumonia, in addition to more severe and laboratory-proven, but much less common, pneumococcal bloodstream infection and meningitis (Cutts et al., 2005). Even in a low disease burden setting like Finland, the overall impact of pneumococcal conjugate vaccine (PCV) on clinical syndromes not associated with bloodstream infection was much greater, despite lesser reductions in these outcomes, than impact on invasive pneumococcal disease detected by blood culture (Palmu et al., 2018).
Long-term morbidity is as important, or in some cases more important, as a measure of impact than premature mortality for some vaccine-preventable infections, such as poliomyelitis (post-polio residual paralysis), as well as central nervous system infections such as encephalitis and subacute sclerosing panencephalitis (measles) and bacterial meningitis (Hib, pneumococcal, and meningococcal vaccines). This is not well captured in vaccine trials and is difficult to fully capture in post implementation studies, especially in low-resource settings, due to a loss of follow-up or a lack of access to specialized assessment of functional and educational outcomes (Greenwood, 2014).
Beyond this, Bloom and colleagues have pointed out that there are a range of long-term impacts of importance to the broader economy, such as behavior-related productivity gains, which are relevant to measurement of the economic benefit of vaccines but are usually not considered (Bärnighausen et al., 2014; Bloom et al., 2018). Out-of-pocket health care costs associated with hospitalization can be substantial and disproportionately affect the poorest population groups; thus vaccines, which reduce or eliminate these costs, can have a role in poverty reduction (Riumallo-Herl et al., 2018).
Some long-term impacts are readily understood, such as improved school performance resulting from not experiencing cognitive impairment from meningitis. The validity of attributing benefits with unclear causal pathways to a vaccine effect may be difficult to disentangle from apparent benefits due to confounding variables – that is, a “healthy vaccine effect”, whereby more advantaged or proactive members of disadvantaged communities are more likely to ensure that their children receive all offered vaccines in a timely fashion [i.e., family characteristics are responsible for observed differences with incompletely vaccinated children rather than the vaccine(s) per se]. Examples of such reports include the association of measles vaccination with higher school enrollment in Bangladesh and receipt of all Expanded Program on Immunization (EPI) vaccines in the Philippines being associated with higher scores on cognitive testing (Bärnighausen et al., 2014; Bloom et al., 2011). More studies are needed to evaluate the contribution of vaccine programs to behavior-related productivity gains and macroeconomic effects, particularly in low- and middle-income countries, but are seldom considered (Deogaonkar et al., 2012).
All these considerations relate to the potential to underestimate population-level vaccine impact. However, it is also important to be mindful of the potential for vaccine impact to be overestimated, especially by time series comparisons of administrative data for relatively nonspecific outcomes, such as all cause pneumonia or all cause gastroenteritis before and after vaccine introduction, which are most liable to bias and confounding (Bruhn et al., 2017).
Impact of Vaccines in the Expanded Program of Immunization
The Expanded Program of Immunization (EPI) was established in 1974 to provide universal access to six life-saving vaccines [polio, measles, diphtheria–tetanus–pertussis (DTP), and Bacille Calmette–Guerin (BCG)] and built on the success of the smallpox eradication program (Okwo-Bele & Cherian, 2011). The smallpox experience had demonstrated that in many countries, significant enhancements in health infrastructure and personnel as well as dedicated resources were needed to deliver community-wide immunization programs, enhanced by periodic broad campaigns aimed at “hard-to-reach” groups. Smallpox remains the only example of an infection eradicated globally, with estimated recurrent annual savings since eradication in 1979 of $US300 million (Ehreth, 2003). Two diseases currently being targeted for elimination and ultimate eradication by vaccination do not share smallpox’s characteristics of low transmissibility (measles) and low asymptomatic infection (poliomyelitis) and so are much more challenging, but success would yield even greater recurrent dividends to global health, not just for children but across the age spectrum.
The Global Polio Eradication Initiative began in 1988 when polio paralyzed more than 1,000 children worldwide every day. Since then, more than 2.5 billion children have been immunized against polio. Type 2 poliovirus was eliminated in 1999 and the most recent case of type 3 was identified in 2012. In 2018, only three countries (Nigeria, Afghanistan, and Pakistan) have never stopped polio transmission, and global incidence of polio cases has decreased by 99%. Eliminating the last 1% of polio cases has been made difficult by conflict, hard-to-reach populations, and poor infrastructure. The “polio endgame” strategy involves sequential introduction of inactivated polio vaccines, with the aim of fully replacing live attenuated oral vaccines and eliminating vaccine-derived strains (Parker et al., 2015; Figure 1).
Since the inclusion of measles vaccine in the EPI in 1974, there have been impressive increases in single-dose measles vaccine coverage by 2 years of age from less than 20% to around 85% by 2015 (Moss, 2017). However, the milestones set by the World Health Assembly in 2010 for global coverage by 2015 (>90% nationally and >80% in every district) and reduction in measles cases (to less than five per million population) were not met, except for one WHO region (the Americas). Global measles deaths, modeled on reported cases, vaccine coverage, and country-specific mortality ratios, are estimated to have decreased by about 80%, from around 650,000 to 134,000 per year between 2000 and 2015 (Patel et al., 2016). In 2010, almost two thirds of measles deaths occurred in the African region and one quarter in South East Asia, with 53% of the estimated 21 million infants who had not received measles vaccine living in six countries (India, Nigeria, Pakistan, Indonesia, Ethiopia, and the Democratic Republic of Congo) (Simons et al., 2012). Figure 2 shows estimated reductions in measles deaths from increasing vaccine coverage from 2000 to 2017.
Maternal and Neonatal Tetanus
Neonatal tetanus (occurring within the first 28 days of life) has long been recognized by clinicians as an important cause of neonatal death in resource-poor countries. Cases are often clustered in poor remote communities, where unhygienic obstetric and postnatal practices prevail and access to immunization is poor. In the late 1980s, WHO estimated that more than 1 million deaths each year were attributable to tetanus, with an estimated 787,000 deaths due to neonatal tetanus alone in 1988 (Roper et al., 2007).
In 1961, a trial in Papua New Guinea first demonstrated that the use of two or more doses of tetanus toxoid during pregnancy could prevent neonatal tetanus (Schofield et al., 1961). In the mid-1970s, tetanus toxoid vaccination of pregnant women was included in WHO’s EPI. In 1989, the 42nd World Health Assembly called for the elimination of neonatal tetanus. A decade later progress toward elimination was slow and WHO, UNICEF, and UNFPA relaunched the program as the Maternal and Neonatal Tetanus Elimination (MNTE) initiative, now including elimination of maternal tetanus as a goal.
The WHO estimated that in 2015, there were 34,019 infant deaths due to tetanus, a 96% reduction from the late 1980s. As of March 2018, 45 out of 59 countries identified as being at risk of MNT in the year 2000 had reached elimination status. Fourteen countries, mostly in Africa, had still not reached MNTE status at that time (Burgess et al., 2017; Figure 3).
Although cases and deaths from pertussis were declining in high-income countries for many decades before vaccines were available, dramatic decreases attributable to vaccines can be convincingly demonstrated (van Wijhe et al., 2016). Since 1980, the EPI is estimated to have improved uptake of three doses of DTP vaccine from less than 20% in low- and middle-income countries to around 80%. In high-income countries, uptake is estimated to have also improved from an average of around 60% to more than 90% (Levine et al., 2011). Surveillance of pertussis is lacking, especially in low- and middle-income countries, so estimates of pertussis deaths rely on modeling using age and country-specific data on vaccine coverage, vaccine effectiveness, and case fatality rates. In 1999, there were an estimated 390,000 deaths in children under 5 years of age, with 200,000 in Africa (Crowcroft et al., 2003). An updated model (taking into account increased DTP coverage, substantial protection against death from fewer than three doses of DTP, and country-specific mortality profiles) estimated that in 2014 around 160,000 deaths occurred in children younger than 5 years globally. Estimated reductions in mortality since 1999 were driven by improvements in DTP coverage, with India (82% coverage but a large population and high mortality) and Nigeria (smaller population but coverage of around 55%) having the highest estimated burden of pertussis deaths, about half (53%) occurring before 12 months of age (Yeung et al., 2017).
In the 1970s, before DTP vaccines became easily accessible and used worldwide, an estimated 1 million cases of diphtheria occurred each year in low- and middle-income countries, including 50,000–60,000 deaths. After the establishment of the EPI in 1974 and steadily increasing DTP coverage, the total number of diphtheria cases reported to WHO reduced by >90% during the period 1980–2000 (World Health Organization, 2017b).
Bacille Calmette–Guerin (BCG) vaccine has well-documented efficacy against disseminated tuberculosis in infants and children, but variable efficacy against adult pulmonary tuberculosis and other mycobacterial diseases. A meta-analysis in 2006 estimated that the approximately 100 million BCG doses given to infants worldwide in 2002 prevented about 30,000 cases of tuberculous meningitis and 11,500 cases of miliary tuberculosis, with numbers of prevented cases highest in South East Asia (46%), sub-Saharan Africa (27%), and the Western Pacific (15%) (Trunz et al., 2006).
Impact of Vaccines in the Global Vaccine Action Plan (2012–2020)
In 2013, an estimated 6.3 million children died before reaching their fifth birthday; almost all of these deaths occurred in low-income and middle-income countries. Pneumonia, diarrhea, and malaria are the principal causes of child deaths from infectious diseases, with infection responsible for about one third of deaths in children under age 5. In May 2012, the World Health Assembly endorsed the Decade of Vaccines—Global Vaccine Action Plan (GVAP). The GVAP set five targets, including national DTP3 (three doses of diphtheria–tetanus–pertussis vaccine) immunization coverage of 90% by 2015, with no district having coverage less than 80%.
It has been estimated that if the coverage targets for introduction and sustained use of 10 vaccines in 94 countries during the decade of vaccines (2011–2020) could be met, approximately 25 million deaths would be averted compared with a hypothetical scenario of zero coverage. The estimated numbers of deaths potentially averted in countries eligible for Global Alliance for Vaccines and Immunization (GAVI) support through achieving high vaccine coverage in routine programs was greatest for measles vaccine, supplemented by special immunization campaigns (about 13 million), followed by hepatitis B vaccine (about 5 million), pneumococcal vaccine (1.5 million), Hib vaccine (1.4 million), rotavirus vaccine (800,000), human papillomavirus (HPV) vaccine (525,000), rubella vaccine (400,000), and a campaign to deliver meningococcal serogroup A vaccine (250,000) (Lee et al., 2013). A summary of the global situation prior to commencement of GVAP is shown in Figure 4.
Disease due to hepatitis B virus (HBV) occurs worldwide, with active infection identified by the presence of hepatitis B surface antigen (HBsAg). Acute hepatitis occurs in about 1% of HBV infections acquired perinatally and 10% of infections acquired in childhood, whereas ultimate progression to chronic infection, liver cirrhosis, and liver failure occurs in 80–90% of perinatal and 30–50% of childhood infections. In 2015, it was estimated that almost 890,000 persons died from complications of chronic hepatitis B infection (90% from hepatocellular carcinoma or cirrhosis, typically more than 30 years after acute infection). This is why the estimated number of lives saved by routine hepatitis B programs is so high, although there is a long lag time for these results to be achieved. Global prevalence estimates of chronic hepatitis B infection are based on seroprevalence of HBsAg, which varies from around 6% in the highest prevalence areas (African and Western Pacific regions) to less than 1% in the lowest endemicity areas in Europe.
Major progress in reducing the global burden of HBV has been achieved through hepatitis B vaccines, first available in 1984 (World Health Organization, 2017a). Between the 1980s, when hepatitis B birth programs first began, and 2015, estimated global prevalence of HBsAg positivity among children less than 5 years of age decreased by 72%, from 4.7% to 1.3% (World Health Organization, 2017a). Mathematical models of the impact of hepatitis B vaccine programs estimate that around 14 million cases of chronic HBV infection have been prevented in children under the age of 5 years worldwide (World Health Organization, 2017a). Comparison of country reports of changes in seroprevalence of HBsAg more than 15 years after introduction of hepatitis B vaccination programs found that universal immunization of infants had greater impact at the population level (reducing prevalence by around 75%) than targeted immunization of children of mothers known to have chronic HBV infection (by about 67%) (Whitford et al., 2018). In 2016, the World Health Assembly set a milestone of less than 1% global prevalence of HBsAg among children less than 5 years of age by 2020 and less than 0.1% by 2030. Achievement of this ambitious goal will require delivery of hepatitis B vaccine at the time of birth (estimated to occur in about 30% of births in countries where it is recommended), and further increases in coverage in countries where universal hepatitis B vaccine is given as combination vaccines, including hepatitis B, estimated at 84% for three doses in 2015 (World Health Organization, 2017a).
Hib and Pneumococcal Conjugate Vaccines
GAVI-initiated accelerated introduction plans for pneumococcal conjugate (PCV) and Hib conjugate vaccines between 2003 and 2005 aimed to shorten the gap of 20 years between 80% coverage in high-income and low-income countries, seen for access to Hib vaccines, to around 5 years for PCVs (Levine et al., 2011). In 2000, pneumococcus was estimated to be responsible for 735,000 deaths (O’Brien et al., 2009) and Hib for 363,000 deaths (Watt et al., 2009) worldwide, primarily due to meningitis and pneumonia. In the pre-vaccine era, incidence of Hib meningitis was three- to fourfold higher than pneumococcal meningitis in high-income countries, but in low-income countries, especially in Africa, incidence of Hib and pneumococcal meningitis was similar (McIntyre et al., 2012). In low-income countries, meningitis mortality was much higher (over 50%), but in high- and low-income settings, severity in survivors of pneumococcal meningitis was greater than Hib (around 25% with readily documented long-term sequelae vs. 10% for Hib survivors) (Edmond et al., 2010). For pneumonia, estimates are subject to more uncertainty, as diagnostic specimens are typically not available or negative, so estimates of the proportion due to Hib or pneumococcus must be inferred from clinical trial data. The most recent estimates, from 2015, were derived from modeling country- and pathogen-specific cases and deaths and applying vaccine adjustments for coverage, efficacy, and serotype distribution in the context of major increases in the number of countries adopting these vaccines since 2000 (Wahl et al., 2018).
Hib vaccines were introduced in most high-income countries in the 1990s and resulted in near eradication of Hib as a cause of meningitis (McIntyre et al., 2012). Figure 5 shows changes in the incidence of meningitis by age in the United States post introduction of Hib and pneumococcal vaccine programs (McIntyre et al., 2012)
Pneumonia, although an uncommon manifestation of invasive Hib disease in high-income countries, was documented with and without Hib bacteremia in a vaccine trial in The Gambia, where efficacy of Hib vaccine against all radiologically confirmed pneumonia was around 20% (Mulholland et al., 1997). Enhanced surveillance in The Gambia, which achieved high vaccine coverage following introduction of Hib vaccine into the EPI schedule in the late 1990s, demonstrated eradication of Hib disease, with incidence declining from 200 per 100,000 children under 1 year of age in the pre-vaccine era to zero (Adegbola et al., 2005).
Estimates of the proportion of pneumonia due to Hib from The Gambia trial have been combined with estimates of meningitis and non-meningitis, non-pneumonia cases and stratified by country mortality profiles to derive global estimates of total Hib disease and vaccine impact (Wahl et al., 2018). It was estimated that deaths due to Hib disease declined by 90% (95% CI 78–96%) between the year 2000 and 2015. In 2015, there were an estimated 29,500 deaths, with the number of countries using Hib vaccine increasing from 60 in 2000 to 192 in 2015. Overall, it was estimated that Hib vaccine, through both direct and indirect effects, prevented around 1.2 million deaths between 2000 and 2015. China remained one of only three countries worldwide which had not introduced Hib vaccines in 2015, along with Thailand and Russia. China alone was estimated to have 1,000 deaths per year due to Hib disease (Wahl et al., 2018)
Pneumococcal conjugate vaccines were introduced in 52 GAVI-eligible countries, many with a very high estimated pneumococcal disease burden, between 2010 and 2015. A recent model used data from meta-analysis of PCV trials and observational studies to generate estimates of pneumococcal meningitis, pneumonia, and non-meningitis–non-pneumonia cases, stratified by country mortality profile, which were then used to derive global estimates of pneumococcal disease burden and vaccine impact according to PCV coverage (Wahl et al., 2018). The model estimated that 250,000 deaths were prevented by PCV use between 2000 and 2015, with more than 95% of these after 2010. Pneumococcal deaths in 2015 were estimated to be 294,000 in 2015 compared with 600,000 in 2000, a reduction of 51% (95% CI 7–74%). Figure 6 shows estimated reductions in Hib and pneumococcal disease and vaccine coverage at the global level from 2000 to 2015 (Wahl et al., 2018)
Importantly, these estimates of pneumococcal deaths and cases were subject to considerable uncertainty (in 2000, 396,000 to 733,000, and in 2015, from 192,000 to 366,000) because vaccine-preventable pneumonia incidence was not well-defined. Reassuringly, detailed studies in one region of a low-income, high-incidence African country (The Gambia) provide evidence of a significant impact post introduction of PCV13 compared with a 2-year baseline period. For invasive pneumococcal disease (IPD), a decrease of around 55% (95% CI 30–71%) was found in children up to 4 years of age, even after accounting for a non-significant increase of 47% in pneumococcal serotypes not contained in PCV 13, in the context of case fatality of around 10% (Mackenzie et al., 2016). The incidence of chest X-ray proven pneumonia was approximately 10-fold higher, and of the most severe clinical category (pneumonia with hypoxia) about fivefold higher than total IPD incidence (Mackenzie et al., 2017). Significant decreases were found in both these syndromes, greater for hypoxic pneumonia (57% in children 2–11 months of age and 72% in children 21–23 months old) than for chest X-ray proven pneumonia (23% and 29% in the same age groups). Overall decreases in all clinically diagnosed pneumonia hospitalizations were substantially lower, but statistically significant (8%; 95% CI 3–13%). However, because total hospitalizations for pneumonia were much greater, the absolute decrease in all hospitalized cases was about twofold greater than for radiologically proven cases. The magnitude of these reductions in IPD and pneumonia is comparable to that documented in high-income countries and gives confidence in the extrapolations made to estimate global reductions - extrapolations driven by high-incidence, high-mortality countries such as The Gambia.
Using data from the Global Burden of Disease study (Khalil, 2017), diarrheal disease was estimated to account for 1.3 million deaths annually worldwide and 0.5 million in children under 5 years, in 2015. Rotavirus was by far the leading cause of death (29%), followed by cryptosporidium (12%) and shigella (11%). Between 2005 and 2015, deaths in children less than 5 years of age attributable to gastroenteritis were estimated to have decreased by 34% due to improvements in nutrition, sanitation, and access to clean water, whereas deaths attributable to rotavirus were estimated to have decreased by 44%, the difference attributed to vaccine introduction (Troeger et al., 2017) For acute gastroenteritis hospitalizations, rotavirus is estimated to account for a larger proportion of cases among children under 5 years of age worldwide (40%) (Burnett et al., 2017).
Despite modest efficacy of the two commercially available rotavirus vaccines in clinical trials in low- and middle-income countries in Africa and Asia compared with earlier trials in high-income countries (Burnett et al., 2017), recognition of potential mortality reductions drove a surge of national introductions, with GAVI funding support from 2012, such that by December 2106, 81 of the 194 WHO member states had introduced rotavirus vaccines into their national immunization programs (Nelson & Steele, 2017). A recent meta-analysis incorporated 57 reports from 27 countries, with 53 reporting hospitalization data (26 from low-mortality countries) and 12 reporting on mortality (11 from medium mortality countries and five from high-mortality countries). For acute gastroenteritis (AGE) hospitalizations, the median reduction was 41% in low-mortality, 30% in medium-mortality, and 46% in high-mortality countries. For AGE mortality in infants, the median reduction in medium-mortality countries was 45%, and in high-mortality countries 30%, an overall reduction of 31% (Burnett et al., 2017). These data suggest that continued rotavirus vaccine introduction into large, high-mortality countries in Asia (India, Pakistan, and Bangladesh) and Africa (Nigeria, Democratic Republic of Congo) will reduce overall AGE mortality even further. Figure 7 shows the impact of rotavirus vaccines on hospitalizations and deaths from all-cause gastroenteritis in countries with low, medium, and high child mortality from a summary of published estimates (Burnett et al., 2017)
Rubella is a leading cause of vaccine-preventable birth defects, notwithstanding recent Zika virus outbreaks (WHO global measles and rubella strategic plan: 2012–2020). Infection during the early part of pregnancy can lead to miscarriage, fetal death, stillbirth, or the development of a constellation of congenital malformations, collectively known as congenital rubella syndrome (CRS). The elimination of rubella is programmatically linked to that of measles, as the two vaccines are usually given in combination, and most cases of rubella are detected through measles surveillance. However, surveillance for rubella infection is more difficult, as it usually presents with milder symptoms, and a significant proportion of those infected are asymptomatic. The GVAP 2011–2020 includes goals to eliminate rubella in at least five of the six WHO regions by 2020.1 In 2016, only 22,361 rubella cases were reported to the WHO, a 97% reduction from the total of 670,894 cases reported in 2000. In the Americas, the last case of CRS was reported in 2009 and the region was verified as free of rubella in April 2015. However, the 2020 goal still seems far away, as transmission is yet to be interrupted in Europe and the Western Pacific, while no elimination targets have yet been set in the other three WHO regions. This contrasts with measles, where all WHO regions have set elimination goals. Rubella elimination globally will require continued improvements in routine immunization services, vaccination campaigns, and rubella and CRS surveillance.
As one of the few vaccines that prevent cancer, the human papillomavirus (HPV) vaccine has great potential to reduce infection-related cancers globally. Oncogenic HPVs cause almost 100% of cervical cancers, 90% of anal, 70% of vaginal, 40% of vulval, 50% of penile, and from 13% to 72% of oropharyngeal cancers (Forman et al., 2012). Cervical cancer accounts for the highest burden of these cancers and the first two prophylactic vaccines, licensed for clinical use in 2006, were developed to target the most common HPV genotypes causing this disease. Currently available vaccines now include a bivalent vaccine (2vHPV) targeting HPV16/18, a quadrivalent vaccine (4vHPV) targeting HPV 16/18/6/11, and a nonovalent vaccine (9vHPV), which also includes the next five most common oncogenic genotypes in cervical cancers (31/33/45/52/58). The 4vHPV and 9vHPV vaccines include genotypes (6,11) causing genital warts.
All HPV vaccines have been demonstrated to be highly immunogenic and effective in preventing infection with vaccine-type HPV. However, measuring vaccine impact requires effective surveillance systems for HPV-related disease, such as cervical screening and cancer registries, and capacity to genotype HPV-associated cancers (Harper & DeMars, 2017). A small number of high-income countries, with high-coverage immunization programs and high-quality surveillance, have demonstrated major decreases in vaccine-type HPV infection prevalence, but the highest global cervical cancer burden (40%) occurs in lower middle-income countries, where HPV vaccine programs are scarce (Harper & DeMars, 2017).
There are 13 serogroups of Neisseria meningitidis, but six (A, B, C, W, X, and Y) are responsible for almost all cases of invasive meningococcal disease (IMD). Accurate estimates of the global burden of meningococcal disease are lacking due to inadequate surveillance in many parts of the world, but it is considered to be endemic globally (Halperin et al., 2012). The predominant strains causing disease vary geographically and over time, with reported incidence ranging from less than 0.5 cases per 100,000 in North America and just under 1 case per 100,000 in Europe, to 10–1,000 cases per 100,000 during epidemic years in Africa (Halperin et al., 2012). In every region, the incidence is highest in children, with infants <1 year of age having the highest rates of disease. Younger school-aged children have lower rates of disease, and a smaller peak in incidence occurs in adolescence.
Nasopharyngeal carriage is thought to be an essential step in the development of IMD. Carriage rates vary by age and setting but are consistently highest in adolescents and young adults. Polysaccharide meningococcal vaccines were developed over 40 years ago, but are limited by their inability to produce immunological memory, poor immunological responses in infants, and lack of impact on nasopharyngeal carriage (Crum-Cianflone & Sullivan, 2016). In contrast, post-licensure studies in a number of countries have demonstrated vaccine effectiveness and indirect protection from use of conjugate A and C vaccines.
Meningococcal C Conjugate Vaccines
In 1999, the United Kingdom was the first country to introduce Men C vaccine into its national immunization schedule, rolled out to all children < 18 years of age. Impact was rapid, with an overall reduction of 86.7% observed in target groups in 2001 compared to 1999. By 2007–2008, there had been a decrease in the number of IMD cases in each age group under 20 years of age, and due to reduction of nasopharyngeal carriage, a > 90% decline in disease in the non-vaccinated population. (Campbell et al., 2009).
Other countries have demonstrated similar decreases in Men C incidence following broad vaccine programs targeting a wide age group. The Netherlands had sharp decreases in Men C incidence after introducing a single dose schedule at 14 months alongside a catch-up campaign for all children and adolescents (de Greeff et al., 2006). Similar outcomes were seen in Australia (Lawrence et al., 2016), and Canada (De Wals et al., 2011).
Meningococcal A Conjugate Vaccine
Serogroup A (Men A) has long caused repeated epidemics of IMD in sub-Saharan Africa across multiple countries, from Senegal in the west to Ethiopia in the east, with high endemic incidence during the rainy season, alternating with hyperendemicity during the dry season. Epidemics occur in cycles every 7 to 10 years, with some of the highest incidence rates of disease recorded globally (Halperin et al., 2012).
The disease burden was extremely high, with death and disabling sequalae occurring in 20–35% of cases (Pace & Pollard, 2012). During the 2007 epidemic in Burkino Faso, it is estimated that households spent a third of their gross income per meningitis case and the public health system spent 2% of the national health budget responding to the epidemic (Colombini et al., 2011).
In 2000, the WHO launched an initiative leading to the development of a low-cost conjugate Men A vaccine MenAfriVac. The vaccination program was rolled out initially in Burkino Faso in 2010, vaccinating more than 11 million children and adults in 10 days to achieve >90% coverage. This led to a rapid reduction in the incidence of IMD, with no cases due to Men A recorded the following year (Novak et al., 2012). The incidence of IMD was 2.5 per 100,000 in targeted areas (with no cases of Men A) versus 43.8 per 100,000 in the rest of the country. The initiative was subsequently rolled out to over 26 countries in the meningitis belt, with similar results. Across nine countries in the meningitis belt, the incidence of confirmed Men A disease in vaccinated populations was reduced by more than 99% (Trotter et al., 2017).
Meningococcal B Vaccines
Similarities between the capsular polysaccharide of serogroup B (Men B) strains and human polysialic acid on neural cell adhesion molecules, with the potential risk of immunological cross-reaction, have meant that alternate approaches targeting surface-exposed proteins were needed for vaccine development.
The first such vaccines used the outer membrane vesicles of outbreak strains, initially in Cuba and Norway, but most prominently in New Zealand, which experienced a prolonged epidemic of Men B caused by one predominant strain in the early 1990s. Rates of disease exceeding 50 per 100,000 were documented in Pacific Islanders and > 25 per 100,000 in Maori communities (Loring et al., 2008). The strain-specific outer membrane vesicle (OMV) vaccine developed and implemented to target this epidemic—the MeNZB vaccine (Lennon et al., 2009)—was rolled out sequentially by region to all people under 24 years, clearly hastening control of the epidemic, although it was by then declining (Galloway et al., 2009). In 2013, a new four-component vaccine against Men B (Bexsero) was approved by the European Medicines Agency, containing the same OMV protein used in New Zealand, with three additional recombinant proteins identified through “reverse vaccinology”: the Neisseria-binding antigen (NHBA), the Neisseria adhesin A (Nad A), and the factor H binding protein (fHbp). Bexsero was introduced into the United Kingdom immunization schedule in September 2015, and within 10 months the vaccine was found to be 83% effective against all Men B cases in vaccine-eligible infants (Parikh et al., 2016). In Quebec, Canada the same vaccine was used in a one-off campaign in May 2014 to combat an outbreak, targeting a broad age group—the campaign led to an estimated 78% reduction in Men B disease incidence (De Wals et al., 2017).
The focus of Millennium Development Goal 4 was a decrease in under 5 years of age mortality by two thirds between 1990 and 2015. During that time, the mortality halved, representing an annual decline of around 5% per year globally. However, annual neonatal mortality has only reduced by around 3% per year, and it is estimated that neonatal mortality in 2015 accounted for 44% of under 5 mortality (Sobanjo-ter Meulen et al., 2015).
Maternal immunization has been shown to be a highly effective strategy for reducing early infant mortality from tetanus and is recommended for influenza and pertussis. Vaccines under development show great promise to protect against severe early infant infection due to group B streptococcus and respiratory syncytial virus (RSV) (Sobanjo-ter Meulen et al., 2015).
It has been estimated that in 2008, between 28,000 and 110,000 children died from influenza infection globally, 99% in low- and middle-income countries. Maternal immunization has been demonstrated to be effective in reducing the burden of disease in separate clinical trials in Bangladesh (VE 63%) (Zaman et al., 2008) and South Africa (VE 48.8%) (Madhi et al., 2014). The cost and logistic requirements for seasonal vaccination mean that implementation of maternal influenza immunization programs in high burden settings is out of reach, at least in the near term. Such programs are recommended and funded in many higher-income countries, but population-level impact data are currently lacking.
In high-income countries with long-standing high infant DTP coverage, such as the United Kingdom, the United States, and Australia, absolute numbers of laboratory-proven pertussis deaths are very small compared with the pre-vaccine era, and almost all occur before 3 months of age (Chow et al., 2016). This has led to national recommendations for universal maternal immunization with adult-formulated acellular pertussis vaccine (Tdap) in these and similar countries (Meulen et al., 2017). The most rigorous data on the impact of Tdap-containing vaccine in pregnant women come from the United Kingdom, which rapidly achieved coverage among pregnant women of over 70%, with sustained effectiveness in the 3 years since the introduction, and VE against death was estimated at 95% (95% CI 79–100%) (Amirthalingam et al., 2016). The extent to which addition of pertussis vaccine to current maternal tetanus programs could also contribute to decreased neonatal mortality in high mortality countries is uncertain, but timely high infant coverage for DTP must be a precondition for its consideration (Sobanjo-ter Meulen et al., 2016)
Group B Streptococcus
Group B streptococcal (GBS) infection is the single most frequent cause of neonatal sepsis and meningitis globally. It is estimated that 90% of cases occur in sub-Saharan Africa where the estimated case fatality rates are high, at 22%, with the lowest rates of disease in Asian countries (Edmond et al., 2012). Maternal carriage of GBS in the gastrointestinal or genital tract is thought to be a prerequisite for early onset disease, with vertical transmission occurring around the time of birth, so screening and antibiotic prophylaxis during labor is a widely recommended approach to prevention of early-onset neonatal disease. With respect to vaccines, the association between low GBS type-specific anti-capsular polysaccharide antibody and invasive GBS disease in newborns has long been known (Baker & Kasper, 1976), and around 560 women have received a trivalent CRM197-conjugated GBS vaccine during pregnancy in clinical trials, which showed it to be immunogenic. Maternal immunization for GBS could prevent early- and late-onset disease, but significant knowledge gaps remain around the immunobiology, which need to be addressed before widespread vaccination programs can be developed (Heath et al., 2017).
Respiratory Syncytial Virus
RSV causes an estimated 34 million episodes of lower respiratory tract infection in infants and children younger than 5 years of age annually and is thought to cause between 3% and 9% of all deaths due to lower respiratory tract infections in infants globally (Heath et al., 2017). Of all RSV-associated deaths, about 99% are estimated to occur in low- and middle-income countries, most in infants less than 6 months of age (Scheltema et al., 2017). There are currently no effective treatments for RSV infection and no licensed vaccines, although a number of RSV vaccine candidates have reached phase III trials, including one administered in the third trimester of pregnancy (Heath et al., 2017; Munoz, 2015). However, maternally derived antibody is unlikely to provide substantial protection for infants older than 6 months of age, limiting impact on RSV disease overall (Munoz, 2015).
New Vaccines for High Burden Diseases
Tuberculosis (TB) remains the leading infectious cause of death worldwide, with estimates from 2016 that 10.4 million people developed active TB, approximately 1 million of them children (World Health Organization, 2014). The burden of disease in children is likely underestimated as most cases are sputum smear negative (Walls & Shingadia, 2003) and the highest burden of tuberculosis is in low- and middle-income countries with limited diagnostic facilities. Although as noted, Bacille Calmette–Guerin (BCG) vaccine is estimated to prevent 120,000 childhood deaths each year (Trunz et al., 2006), estimates of vaccine efficacy vary widely by geographic area and are substantially higher in disseminated TB (52% to 100% for tuberculous meningitis and miliary TB) than pulmonary TB (2% to 80%). The World Health Organization has developed an “end TB” strategy, and substantial progress has been made in new vaccines for prevention of reactivation disease in adolescents, which is in turn important for reducing exposure to vulnerable infants and children (Vekemans et al., 2019).
In the past two decades, since the late 1990s, malaria control programs in sub-Saharan Africa have increased substantially, driven by an approximate 20-fold increase in funding through the Roll Back Malaria initiative to support insecticide-treated bed nets, indoor residual spraying, and more timely diagnosis and treatment of malaria cases. Bhatt et al. estimated that between 2000 and 2015 such interventions halved the prevalence of Plasmodium falciparum infection, with incidence of clinical disease falling by 40% (Bhatt et al., 2015).
In 2014, the first report of a malaria vaccine candidate to complete a phase III trial—RTS,S/AS01—was published (Penny et al., 2016). It demonstrated moderate efficacy against clinical cases over 18 months post third dose of 46% (95% CI 42–50%) in children 5–17 months at first vaccination and 27% (95% CI 20–32%) in infants. Since the burden of malaria in many countries is very high, even a vaccine with modest efficacy may provide public health benefit, and modeling has suggested potential cost-effectiveness at an assumed coverage of 90% for the first three doses and 72% for a fourth dose (Penny et al., 2016). The Malaria Vaccine Implementation Program (MVIP) has been set up to operationalize the recommendations of the WHO for subnational pilots for the implementation of the malaria vaccine in areas of moderate to high malaria transmission in Africa. Pilot programs in Ghana, Kenya, and Malawi to evaluate the implementation of RTS,S/AS01 in the context of their EPI programs began in 2019. Evaluation of these pilot studies will be crucial in informing the potential for widespread rollout of this vaccine (World Health Organization, 2016).
Improving Immunization Equity
Examples of vaccine programs reducing inequalities in health outcomes can be found in high- and low- and middle-income countries. In the United States, within 4 years after introduction of pneumococcal conjugate vaccine, incidence among Black children <2 years of age decreased from 3.3 times higher than among White children to 1.6 times higher (Flannery et al., 2004). Similar reductions in disparities in rates of disease have been seen in high-incidence Indigenous communities in high-income countries, such as Aboriginal children in Australia (Menzies et al., 2004) and Maori children in New Zealand (Walls et al., 2018).
Some of the greatest impacts of immunization programs in reducing health inequality have come about in low- and middle-income countries. In rural Bangladesh, post a measles vaccination campaign, the 2.6-fold higher all-cause mortality in unvaccinated children from the poorest households was reduced to 1.5 times in vaccinated children. (Koenig et al., 2001). In India, consistently lower immunization coverage rates for BCG, DTP, and measles for girls between 1992 and 2006, despite overall increasing coverage for both boys and girls (Corsi et al., 2009) was largely eliminated during universally targeted campaigns to deliver oral polio vaccine (Corsi et al., 2009).
Despite this potential, challenges remain. In a summary of surveys of DTP3 coverage in 1-year-olds from 70 countries from 2005 to 2011, the greatest differences in coverage between children in wealthiest (Q5) and poorest quintiles (Q1) was 64% in Nigeria (Hinman & McKinlay, 2015). If a difference of <5% between Q5 and Q1 is considered to represent equity, only one third of the 70 countries had achieved equity. The Global Alliance for Vaccines and Immunization (GAVI) established an equity goal for DTP3 that coverage in Q1 should not be >20% lower than Q5. In 2013, it was estimated that 57% of GAVI-supported countries had met this goal.
Enormous gains in child health have been made, especially in countries in the world with the highest mortality rates, since strengthening of the Expanded Program of Immunization (EPI) began in 1974. Measured by reductions in child mortality, these gains have been greatest for measles, and as measured by reductions in long-term morbidity, for polio, both diseases targeted for elimination. There is similar strong evidence of global public health impact through implementation of programs using vaccines against hepatitis B, protein conjugate vaccines against Haemophilus influenzae type b, Streptococcus pneumoniae, and in the African meningitis belt, group A meningococcal and rotavirus vaccines. Significant challenges remain for the endgame for polio, the next stage in elimination of measles and rubella, and mechanisms for funding and delivery of more expensive vaccines, especially in countries transitioning from eligibility for GAVI support (Cernuschi et al., 2018). Public health impact will be maximized by addressing gaps in supply and delivery within and between countries hampering achievement of maximum benefit from vaccines targeted by the Global Vaccine Action Plan, notwithstanding exciting developments on the horizon for significant diseases such as malaria and tuberculosis.
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