Young kid waiting for his turn to be vaccinated at a public health center. Photo by Hyderus-FINN Partners
An Exclusive Authored by N. Guiso, U. Heininger, M.L. Avila-Agüero, U. Thisyakorn, C.H. Wirsing von König
Infant vaccination has been a cornerstone of global health, demonstrating over more than 100 years the health and socio-economic benefits of the reduced burden of infectious diseases. Yet, despite being the most cost-effective intervention after hygiene improvements, vaccination has repeatedly faced multiple challenges in its implementation. From the difficulty of ensuring sustainable and equitable access to vaccines, to the programmatic complexity of an increasing number of vaccine-preventable diseases and socio-cultural challenges to vaccine uptake, various factors continue to jeopardize the optimal benefits of vaccination.
Pertussis, also known as whooping cough, used to be one of the primary causes of childhood disease and death worldwide until the 1980s. Vaccination has since successfully reduced the overall burden and mortality from pertussis1, yet it remains among the ten major causes of mortality in children < 5 years-old2. Modelled estimates suggested as many as 116,510 deaths globally in 20193. In fact, as early as twenty years after generalized vaccination, epidemiologic trends, first in the USA4, then in France5 and in other European countries, showed that the disease was still not sufficiently controlled.
There are numerous factors that contribute to the issue: 1) the waning of the protection elicited by infection or vaccination, 2) the absence or low uptake of regular vaccine booster doses beyond early childhood, 3) demographic dynamics such as the aging of previously unvaccinated cohorts exposed to the intense pre-vaccination force of infection, along with 4) high transmissibility of the pathogen. These factors coalesce to rebuild the pool of susceptible individuals after initial vaccine introduction.
Individuals not only become ill with pertussis but also intensify the circulation of the pathogen across age groups, inducing a shift of the burden towards unvaccinated individuals. The latter may be too young to be vaccinated or be under-vaccinated because they do not have access to, are not eligible to, or chose not to receive vaccination, including boosters.
Pertussis is highly transmissible and natural infection or vaccination does not produce life-long immunity. As a result, its control at the population level requires a high rate of vaccine-induced protection across age groups. Modelling of the pertussis epidemiology in Massachusetts, USA, has shown that suboptimal vaccination across age groups has resulted in the resurgence observed across the 2010-2020 period6.
Data from outbreaks across the 2010s have shown that large-scale outbreaks are still an ongoing issue. California for example had its worst outbreak in 60 years in 20107. While the disease had nearly disappeared during the COVID-19 pandemic, likely owing to non-pharmaceutical interventions and possibly under-detection, since 2022, sizeable outbreaks have re-started to occur on all continents. The patterns observed in these outbreaks reflect the same trends as observed in the 2010s.
On one hand, in high-income countries and some middle-income countries, vaccine coverage rates are close to, or above 90% with the primary series in infancy. This has shifted the burden of pertussis to infants too young to be vaccinated (especially those whose mothers have not received a booster vaccine during pregnancy), and older children, adolescents and adults in the absence of booster vaccinations.
Outbreaks in the UK8, Denmark9, Spain10, or Russia11 in 2023-2024 followed this pattern. On the other hand, many low- and middle-income countries have struggled with maintaining or achieving the necessary high vaccine coverage rates (VCR). Most do not offer comprehensive booster vaccination yet, and often have limited surveillance capacity. As a result, these countries typically have a heterogeneous and incomplete understanding of the burden of pertussis and its distribution.
As observed in the 2022-2024 outbreaks in South Africa12,13,14, Indonesia15 and the Philippines16, where suboptimal infant VCRs persist, the disease and its associated mortality likely continue to affect infants of various ages, including of the age to be vaccinated, along with older age groups.
Contrary to pertussis, a respiratory bacterial disease for which neither infection nor vaccines induce long-term protection, polio is a rare yet devastating neurological complication of a just as highly infectious enterovirus, which induces strong and long-lasting immunity as an infection and as a vaccine. Vaccination has reduced polio cases by over 99% since its introduction. More than 40 cases of wild-type polio have been reported in 202417. We may be closer to eradication, but reductions in VCR have placed this goal in jeopardy.
The continued use of oral polio vaccine (OPV) in settings struggling to achieve and maintain high VCRs and the challenges encountered in the discontinuation of OPV2 vaccines have resulted in persistent circulation of vaccine-derived polioviruses (cVDPV18) which are the cause of more than 90% of cases of paralytic polio today.
Yet, even following eradication, inactivated polio vaccine (IPV) will continue to be a necessary component of routine immunization (RI) due to the potential for resurgence that may arise from issues such as reservoirs of wild-type or vaccine-derived virus and disease slipping by surveillance programs, or from contamination from stockpiles of the virus.
The high infectiousness of B. pertussis and poliomyelitis virus requires VCRs exceeding 90% for all doses and – in the case of pertussis – regular immune boosting to ensure durable protection to control the diseases and avoid large outbreaks19,20,21,22 as highlighted by global vaccine targets.
The rapid resurgence of pertussis incidence in the UK following infant VCR decrease in the wake of the whole-cell pertussis vaccine safety scare in the 1970s23, or the re-appearance of cases among young children in Australia after the country removed the toddler booster dose of pertussis vaccine in 2003 should serve as historical demonstrations that compliance and timeliness for all doses of the recommended pertussis vaccination schedule are essential to pertussis control24,25.
Unfortunately, not only are we not reaching these targets globally, but VCRs have been decreasing in countries across the globe and the COVID-19 pandemic made matters worse26. There had been progress in the WHO SEARO region with a significant improvement in VCR from 2010 to 2019, but the COVID-19 pandemic pushed it back to 82%, comparable to the level observed in 2010. This has since risen to 91% in 2022, returning to pre-COVID-19 levels27. But post-COVID19, most RI systems have still not recovered.
There had been a notable decline in VCR in the Americas in recent years, with DTP-3 vaccination, used as a benchmark for VCR, reported to have dropped from a high point of 96% in 2015 to 77% by 2022, by which time it had started to recover from a low of 68% in 202127. Even in HICs such as France, there were delays in RI due to the pandemic28. UNICEF estimates that 67 million children missed out entirely or partially on RI between 2019 and 2021; 48 million of them missed out entirely29. Global and national figures of vaccine coverage reported by UNICEF, WHO or national institutions often are not a complete representation of the heterogeneous, subnational situations.
Numerous countries of all socio-economic development strata face situations where, even if country-level infant VCRs are high, communities with low VCRs, often for a variety of reasons, pose a challenge to disease control creating fertile ground for outbreaks. This had already been observed in the 2010s, with a number of outbreaks in North America. Communities with high vaccine exemption rates were found to exacerbate circulation of the pathogen and concentrated initial outbreaks eventually spilled into the broader community30,31,32,33.
Recent post-COVID-19 epidemiology of pertussis is demonstrating this once more, with instances in Israel and Thailand, where outbreaks in 2023 were initially concentrated among poorly vaccinated religious communities 34,35.
While the COVID-19 pandemic has wreaked havoc in healthcare systems, including vaccination programs, the difficulty many countries face in reaching and sustaining high VCRs has been a long-standing issue that has had an increasing impact in recent years. Suboptimal VCRs can have multiple causes, and the 5 As principle36 (Access, Affordability, Awareness, Activation, Acceptance) provides an excellent framework for evaluating them. Access, or lack of it, refers to various parameters of healthcare and vaccination services which may impact the capability of individuals to receive vaccination such as distance and location, hours of opening, staffing and vaccine stock availability.
Affordability denotes the ability of individuals to afford vaccination, both in terms of financial and non-financial costs, for example, in terms of time away from work to receive the vaccine. While these first two parameters may vary from country to country, diphtheria, tetanus, pertussis and polio vaccinations have long been established as the cornerstone of vaccination programs in all countries. The framework’s concept of awareness encompasses the extent and limitations in the knowledge of disease risk and of the vaccination schedule, which can affect the willingness and motivation to vaccinate, leading to complacency.
Activation is related to awareness as it refers to the motivation of parents and healthcare providers, through reminders or nudges towards ensuring complete and timely vaccination of the infants. In this regard, the role of healthcare providers in activating parents towards vaccinating their children is essential. Issues such as healthcare providers opposing mandatory vaccination (as demonstrated in a study from Switzerland37) have further cemented some individuals against vaccination, impacting VCR.
Finally, acceptance has likely become one of the core factors affecting vaccine uptake, notably in the wake of the COVID-19 pandemic. Vaccine hesitancy is associated with a lack of trust in vaccine safety and science, and skepticism about vaccine efficacy38,39. It was increasingly affecting VCRs before the COVID-19 pandemic, but the large-scale vaccination campaigns against COVID-19 further fueled vaccine hesitancy40.
The value of combination vaccines has been long recognized and explains why pertussis vaccines have been combined with other antigens in a single injection practically since their development. With combined pediatric vaccines, children benefit from fewer injections, resulting in less discomfort, fewer potential episodes of adverse effects, and improved adherence to vaccination schedules41. For parents, acceptability has been shown to be higher when appointments are reduced through fewer injections42.
Studies in the Gambia and South Africa documented concerns among parents about a child receiving more than two injections in a single visit43,44. The fewer injections afforded by combination vaccines also mitigate productivity loss due to medical appointments for parents. From the perspective of healthcare providers, fewer injections reduce the time imposed on medical staff for the administration – a critical advantage in low-resource settings – while reducing administrative burden and potential for errors and injuries.
For the overall health system, not only do combination vaccines ease the logistical management of vaccines (e.g. cold chain management, procurement and distribution administration), and open up the RI programs for new vaccines, but they have also been shown to improve VCRs for all covered diseases41,45,46, reducing the potential for outbreak occurrence, and in turn, potentially easing the burden on the healthcare system.
Until the early years of the 21st century and up to recent years in many countries, pentavalent vaccines were established as the standard of care47. However, different pentavalent vaccines contained different antigens. Pentavalent vaccines developed with whole-cell pertussis vaccine (wP) lacked IPV, an essential element of polio eradication, while pentavalent vaccines produced with acellular pertussis vaccine (aP) lacked Hep B. This divergence meant that gaps and inequities remained globally in the immunization of infants.
Technological advances, first attained with aP vaccines and more recently with wP vaccines, led to the formulation of hexavalent vaccines providing immunization against diphtheria, tetanus, pertussis, hepatitis B, Hib disease and polio with inactivated vaccine in a single injection. This breakthrough holds the promise of providing all infants worldwide with early protection against six diseases, cementing polio eradication efforts into infant RI48.
The introduction of hexavalent in South Africa reduced the number of injections per visit, potentially saving three visits and three Hep B injections while implementing five new vaccines (four IPV + one Hib) into existing RI schedules. This has saved an average of 8 USD per child and 3 USD of additional savings in HCP labor costs and parents’ time. Consequently, combination vaccines help save around 10 USD per child in South Africa49.
While hexavalent vaccines are increasingly viewed as the gold standard of care for infant vaccination, the fundamental difference in pertussis antigen composition between aP and wP-based hexavalent formulations has important implications.
Whole-cell pertussis vaccines are suspensions of the entire Bordetella pertussis organism that has been inactivated. This bacterium is fastidious to grow, and the complexity of its more than 3000 antigens makes it impossible to precisely characterize the composition of the vaccine and its reproducibility50. As a result, different wP vaccines and different batches of the same wP vaccine may contain variable amounts of protective antigens and reactogenic components51.
The use of an optic measure of bacterial density in wP vaccine formulation and of imprecise and poorly controlled potency assays for measurement of potency52 reflects and reinforces this lack of control over the vaccine composition and precludes prediction of its efficacy from potency measures53.
In contrast, aP vaccines are formulated using purified antigens, including at least the pertussis toxin, and one or more adhesins for most aP vaccines. Each antigen is purified and detoxified individually, ensuring the removal of most reactogenic components of the bacterium. The formulation relies on precise quantification of each antigen, resulting in the inclusion of defined amounts of each antigen in the final vaccine51. As a result, the composition of aP vaccines, confirmed through antigen-specific precise evaluation of potency, has proven reliable and reproducible since their development in the 1990s.
This fundamental difference in control over the consistency in antigenic composition of pertussis vaccines has direct implications for their immunogenicity and protective effect. Historical wP vaccines were tested for efficacy in the clinical trials of aP vaccines in the 1990s. These wP vaccines, which are no longer produced, were found to range in efficacy from 36% to 98% for different wP vaccines, as well as for the same wP vaccine in different trials54.
The current wP vaccines have never been tested for their efficacy against pertussis disease in a randomized clinical trial, and the single available study of effectiveness recently conducted in the Central Africa Republic would appear to put their protective effectiveness and duration in doubt55. Furthermore, the inherent difficulty in producing wP vaccines of consistent composition resulting from the difficulty in standardizing the culture of B. pertussis is compounded by the use of inadequate clinical immunogenicity assays in the few clinical trials conducted with the current wP vaccines. These assays are generally semi-quantitative and designed to diagnose pertussis. They are rarely validated for precisely quantifying the immune response to a pertussis vaccine56.
For this combination of reasons, wP vaccines have previously been shown to give variable results between different manufacturers, but also for the same manufacturer with different assays57,58,59. This makes it difficult to reliably evaluate the strength and consistency of the immune response elicited by wP vaccines, let alone comparing immune responses between vaccines.
In contrast, the aP vaccines used in the formulation of currently licensed hexavalent vaccines, regardless of the number of pertussis antigens, demonstrated consistent levels of efficacy in the 1990s clinical trials, and recent real-world evidence has confirmed their continued, consistent effectiveness60,61,62,63. Extensive clinical development plans have yielded a large body of evidence on their immunogenicity. Clinical trials conducted in diverse settings using many of the existing infant vaccination schedules have confirmed through validated immunological assays that currently licensed aP hexavalent vaccines induce robust and consistent immune responses64,65,66.
The immunity induced by pertussis vaccines, wP or aP, as by disease, is not life-long and has been shown to wane over time as illustrated by peaking disease incidence in age groups several years away from their last dose of vaccine67. There has been controversy over a potential different duration of protection elicited by aP and wP vaccines68,69,70. Yet, while several studies have tried to measure the duration of protection afforded by currently used aP vaccines, only very little data exist on the effectiveness, let alone its duration, of currently used wP vaccines55,71,72,73.
Newer studies have clearly demonstrated that neither aP nor wP provides long-lived protection and that a robust booster schedule is required to ensure prolonged protection and disease control55,74,75,76.
The development of aP vaccines was triggered by concerns not only about the reliability and efficacy of wP vaccines but also their reactogenicity. The higher reactogenicity of wP vaccines compared to aP vaccines has long been demonstrated77,78, including the impact it can have on vaccine acceptance and completion of vaccine schedules.
In a Cochrane meta-analysis of historical clinical trials, wP recipients had a 77% higher risk of failing to complete their schedule due to adverse events compared with aP recipients78. The study also found that aP recipients did not have any statistically significant increase in risk of failing to complete their vaccination schedule compared to the placebo control group, indicating a high degree of acceptability.
In more recent evidence, the frequency of adverse events reported in a phase 3 clinical trial following vaccination with one of the current hexavalent wP vaccines was largely higher than with an aP hexavalent vaccine in the same population using the same schedule57,79. In fact, real-world evidence analyzed at the time the Chilean national immunization program transitioned from wP to aP vaccines showed a 67% reduction in the reporting of adverse events80.
This higher reactogenicity of wP vaccines was found to affect acceptance and completion of the infant schedule of vaccination in a recent example of high media coverage of a series of severe adverse event-related hospitalizations and one death following wP vaccination in Vietnam resulting in a significant drop in VCR81.
Hesitation regarding adverse events was also observed in Brazil, where a study in São Paulo state showed a 20% decrease in schedule completeness and timeliness in children of parents who reported a previous adverse event following vaccination compared with parents who did not report an adverse event82.
Finally, the difficulty in ensuring consistent composition of wP vaccines, including in reactogenic components also poses a challenge to the sustainability of VCRs. In two examples in Chile and in El Salvador83,84, a change in the supplier of the wP pentavalent vaccine used in the national immunization programs of these countries resulted in a near doubling of the frequencies of adverse events, including serious adverse events such as febrile seizures and hypotonic-hyporesponsive episodes.
Such unexpected, dramatic increases in the frequency of adverse events can further erode parental confidence in the safety of the vaccines and their willingness to see their child fully vaccinated.
In countries where wP vaccines remain the only publicly funded pertussis vaccines, the higher reactogenicity of wP vaccines poses the risk of lower acceptance and VCR among the poorer segments of the population, leaving infants unprotected against pertussis as well as the other diseases included in the combination vaccines such as diphtheria, as well as polio in hexavalent combinations.
Pentavalent acellular pertussis vaccine introduction in Costa Rica was followed by a marked increase in VCR, this was most prominent among the lowest wealth quintiles. In 2011 the overall coverage among the lowest wealth quintile was 79.2% for the third dose of pneumococcal conjugate. By 2018 this had risen to 94.4%85.
Inequities also arise from the burden of reactogenicity. In countries where aP vaccines are only available to those who can afford to pay for them, the poorer families also have to bear the economic burden of higher frequency and severity of adverse events resulting from publicly funded wP vaccines.
The potentially variable safety and efficacy profile of wP vaccines may also expose infants of lower-income families to inequitable exposure to health burdens due to the increased risk of adverse events and potentially increased risk of disease compared to those who can afford more consistent aP vaccines.
The higher nominal cost of purchase of aP vaccines compared to wP vaccines is often an important limitation to ensuring publicly funded, equitable access to aP vaccines, especially in developing and emerging economies. However, the cost of vaccination programs reaches well beyond the procurement cost of vaccines; it encompasses not only the vaccine purchase but also the costs of its logistical management as well as the cost of managing adverse events following immunization, the cost of VCR catch-up campaigns and the cost of illness resulting from under-vaccination.
Considering the economics of the broader public health budget, the adoption of aP hexavalent vaccines in national immunization programs (NIPs) represents a much smaller premium compared to the purchase price of the vaccines86.
The scientific and technological advances in vaccine production of the last two decades have yielded options for routine immunization that can help achieve the WHO’s Immunization Agenda 2023 to “leave no one behind” and to help ensure infants worldwide receive adequate and complete protection against up to 6 diseases in a single injection.
A purposeful decision needs to be made, however, when deciding to opt for a pentavalent or a hexavalent, and for the type of hexavalent vaccine sourced for a national immunization program. In making this decision, policymakers should consider the following factors.
Multiple injections have been shown43 to be less acceptable to parents, and hexavalent vaccines can reduce this concern. This has been demonstrated across numerous economic settings, including the examples illustrated above in the United States, South Africa, and Gambia.
Evidence has demonstrated time and time again and in every setting that elevated reactogenicity can hinder the achievement and maintenance of the required high VCRs. Besides the higher healthcare costs associated with adverse event management, these lower VCRs may induce increases in the incidence of the disease and increased costs for public health authorities both for disease management and vaccination catch-up.
While these considerations are likely applicable in all settings, the heterogeneous robustness of surveillance settings may mean that local, sentinel surveillance studies with trained pediatricians in selected healthcare facilities may be required to establish convincing evidence.
Hexavalent vaccination presents the opportunity to reduce the number of necessary vaccination doses while optimizing efficiency (resource needs over results achieved). Though up-front costs may be higher, hexavalent acellular vaccination may be more cost-effective in the long run through their contribution to help raise and sustain VCRs.
Costs must be determined on a country-specific basis, and include additional costs incurred through adverse reactions and remediation of suboptimal VCRs (disease costs, catch-up costs).
Reducing the number of zero-dose and under-immunized children, aiming toward the global vaccine agenda
Zero-dose children have increased in number since the start of the pandemic, increasing the risk of disease and creating reservoirs of transmission, typically among geographically isolated and/or economically vulnerable communities. Hexavalent vaccination, as with all the component parts of the vaccine, will reduce long-term disability and impairment. This must be factored into costs.
Hexavalent can help VCR for the six antigens in the same way that pentavalent improved VCR for Hib/Hep B and DTP345. There is a need for high VCR to reduce the risk of polio recurrence. Following the withdrawal of OPV, coverage with IPV will be essential to prevent resurgence. The inclusion of IPV as part of hexavalent vaccination ensures its use in routine immunization and is aligned with the WHO’s recommendations87.
Higher predictability of safety and efficacy of aP vaccines is key in ensuring high National Immunization Programme VCR, and reliability of disease control at the population level. Acellular pertussis vaccines have been used for over 25 years and have a well-established safety, efficacy and effectiveness profile. This is sharply contrasted by the very limited to complete lack of available data for currently used wP vaccines.
Strong pharmacovigilance and surveillance of the disease in countries still using wP vaccines would help in the reassessment of the type of vaccine used in their national immunization programs. These data will increase awareness of the disease for public health authorities and establish the need for robust programs with reliable vaccines.
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