A newly published cost-minimization analysis from Argentina offers one of the clearest economic assessments to date on how immunization budgets should be evaluated [1]. The study, conducted by the CINVE research group, compares two hypothetical hexavalent vaccination strategies, one containing whole-cell pertussis (wP) antigens, the other acellular pertussis (aP) antigens, and reaches a seemingly counterintuitive conclusion: the vaccine with the higher purchase price can result in lower total costs to the health system. These wP vaccines are known to have higher rates of side effects (adverse events), placing a significant additional burden on the healthcare system and society [2].

The findings of the study add to a growing body of evidence from previously published cost-minimization studies and go further than most, modelling wP and aP hexavalent strategies and highlighting the monetary benefits of lower reactogenicity.

A long-held assumption is now being challenged

Where the effectiveness of two strategies (or options) aiming to protect against the same pathogen is assumed to be similar, immunization budget holders will typically focus on acquisition cost alone. But a vaccination program’s costs extend well beyond the product: logistics, cold chain, additional appointments, staff time, adverse event management, and the productivity lost when parents take time off work or travel for care.

The evidence from Argentina suggests that this approach risks overlooking where the greatest costs actually occur: in adverse events and their subsequent consequences.

A global randomized controlled trial by Decker et al. assessed the risk of adverse events between wP and aP [3]. Many adverse events, such as pain, redness, and fever, are far more common among those who receive wP vaccines. Fever rates were between two and nearly five times higher among wP recipients [4]. Primary-series recipients are infants, many of these adverse events lead to primary care visits, generating direct costs to the system and households, along with distress that other studies link to reduced willingness among families to accept vaccination more broadly [2]. The impacts of these adverse events are often overlooked and not factored into budget considerations.

The long-held assumption that whole-cell vaccines are the economical choice is becoming increasingly difficult to defend. Assessed against total health care and societal costs rather than acquisition price alone, acellular hexavalent vaccination increasingly presents as the more favorable option.

The current vaccination situation in Argentina

Argentina’s public schedule currently uses three doses, and a single booster dose of a pentavalent wP-containing vaccine (combined with diphtheria, tetanus, Hib (Haemophilus influenzae type B), and hepatitis B antigens), alongside three IPV (Inactivated Poliovirus Vaccine) doses. This option is available through the public healthcare system; however, Argentina’s immunization program already recognizes the more favorable tolerability profile of acellular (aP) hexavalent vaccines by providing them to certain premature infants through Pan American Health Organization (PAHO) supported programs [5].

Those with the means to purchase the acellular vaccine, with its more favorable tolerability profile, can opt for it through the private market [5]. For most Argentinian infants, however, the wP vaccine remains the default option, as it is offered in the National Immunization Program. Families with private insurance have access to the better-tolerated aP formulation as a matter of course. The burden of adverse events and their associated costs falls disproportionately on the public system and the households it serves.

Can the ‘more expensive’ vaccine be the cheaper option?

The answer, according to the analysis of Argentina, is an unambiguous yes. The upfront acquisition cost of an aP hexavalent vaccine is substantially higher than its wP equivalent. In Argentina’s public sector, the PAHO Revolving Fund price is $21.54 per dose for the aP formulation, versus $4.90 per dose for the wP formulation. On a per-vial basis, the case for wP looks straightforward [1].

But the Argentina study exposes the flaw in this reasoning. The vaccine acquisition cost is only one line item in the budget. Modelling Argentina’s annual birth cohort of roughly 495,000 infants across the public sector (representing 94% of the birth cohort), the wP program’s total societal cost was $70 million: $7 million in acquisition costs, $5 million in programmatic costs, and $58 million in adverse event management. The aP program’s acquisition cost was higher at $32 million, with similar programmatic costs ($5 million), but adverse event management fell to $24 million — enough to bring total societal cost down to $61 million [1].

Total public sector costs fell by $9.1 million (~13.0%) under the aP scheme, driven by a $33.6 million reduction in adverse event management costs. In practical terms, this translated to 533,110 fewer primary care visits, 308,687 fewer emergency department visits, 2,868 fewer hospitalizations, and 1,654,129 fewer missed working days for parents [1].

The cost of adverse events is higher than many assume

The study’s most important methodological contribution may be its rigorous quantification of the costs of adverse events. The paper effectively demonstrates that adverse events are not simply clinical inconveniences. They consume healthcare resources at a scale that is seriously underestimated.

Adverse events management costs accounted for 64% of total costs under the wP hexavalent scheme [1]. It reflects the real-world consequences of administering a more reactogenic vaccine to hundreds of thousands of infants. Pain, redness, fever, prolonged crying, and, in rare but serious cases, seizures and hypotonic-hyporesponsive episodes each generate healthcare resource use: medications, outpatient visits, emergency visits, hospitalizations, and the parental time and travel that accompany them.

Notably, the economic model used adverse event data from Decker et al. 1995 [3]. The estimates from this study report smaller differences between wP and aP vaccines compared with more recent analyses, such as Zhang et al. 2014 [2] and Patterson et al. 2018 [6], which suggest a higher risk in the adverse event profiles of wP vaccination. Consequently, the estimates of savings related to adverse events presented for aP vaccination may be rather conservative.

Argentina is unlikely to be an exception

Comparable findings are emerging across different health systems, procurement models, and income settings. A previous whitepaper from Algeria, discussed in Medika Life [7], demonstrated that acellular hexavalent vaccination has improved vaccination coverage and simplified the vaccination schedule by reducing the number of appointments from 10 to 6. Overall, the higher upfront cost of adopting the new vaccine was offset by around 73% through savings generated by managing adverse events, improved logistics and transportation, and increased parental productivity.

Peru and South Africa saw similar patterns after adopting hexavalent vaccines: higher initial costs were substantially offset by reduced adverse events, lower programmatic expenses, and logistical efficiencies. Peru reported a reduction in logistical costs of nearly 60%, with roughly 44% of the initial cost increase recovered [8]. South Africa achieved overall savings of about $10 per child [9]. Projections from Paraguay and Uruguay estimate overall system savings of $2 million and $16.1 million, respectively, when comparing wP vs aP hexavalent vaccination [10,11].

A potential, and very rare, “double-win” for the health system

Evidence indicates that vaccination should be viewed as an investment, rather than an upfront cost, yielding up to 54 times the initial investment according to the WHO [12]. Much of this return on investment is calculated over a very long period, taking into account costs incurred by the medical system after vaccination, not just acquisition costs. The figure demonstrates the power of vaccines, leading to better health outcomes throughout childhood, fewer missed school days, and, in turn, better prospects later in life.

For a policymaker, on the other hand, the initial cost of a new vaccination program must be justified against a host of other healthcare interventions competing for health system resources. Long-term benefits calculated over many years are often insufficient to justify the expenditure. Because most of the savings in this case come from reducing the direct impacts of adverse events, they are realized in the short term. In addition, the societal costs of adverse events are reduced, with fewer children hospitalized and fewer parents taking time off work to care for sick children.

Healthcare decision-makers are often asked to choose between better outcomes and lower costs. The emerging evidence surrounding acellular hexavalent vaccination increasingly suggests that this may be one of the very rare situations in which both objectives can be achieved simultaneously.

[This consensus paper is based on the findings of a white paper discussing the findings of a group of vaccination experts focusing on pediatric immunization, supported by Sanofi. Intended for professional use.]

References

1. Ignacio Olivera, Eduardo Lopez, Carlos Grau Pérez et al. A cost-minimisation analysis: comparison of acellular versus whole-cell hexavalent paediatric vaccination strategies in Argentina, 16 September 2026, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-11039921/v1]
2. Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews 2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6.
3. Decker MD, Edwards KM, Steinhoff MC, Rennels MB, Pichichero ME, Englund JA, Anderson EL, Deloria MA, Reed GF. Comparison of 13 acellular pertussis vaccines: adverse reactions. Pediatrics. 1995 Sep;96(3 Pt 2):557-66. PMID: 7659476.
4. Casabona, G., Shah, N., Choudhury, J., & Shah, U. (2026). Whole cell and acellular pertussis vaccines – rethinking the evidence. Expert Review of Vaccines, 25(1). https://doi.org/10.1080/14760584.2026.2689606
5. Olivera, I., Pérez, C.G., Lazarov, L. et al. Cost minimization analysis of a hexavalent vaccine in Argentina. BMC Health Serv Res 23, 1067 (2023). https://doi.org/10.1186/s12913-023-10038-0
6. Patterson, J., Kagina, B. M., Gold, M., Hussey, G. D., & Muloiwa, R. (2018). Comparison of adverse events following immunisation with acellular and whole-cell pertussis vaccines: A systematic review. Vaccine, 36(40), 6007-6016. https://doi.org/10.1016/j.vaccine.2018.08.022
7. Medika Life, An Expert Perspective from Algeria on Hexavalent Vaccine Adoption. https://medika.life/an-expert-perspective-from-algeria-on-hexavalent-vaccine-adoption/
8. Seinfeld J, Rosales ML, Sobrevilla A, López Yescas JG. Economic assessment of incorporating the hexavalent vaccine as part of the National Immunization Program of Peru. BMC Health Serv Res. 2022 May 16;22(1):651. doi: 10.1186/s12913-022-08006-1. PMID: 35570278; PMCID: PMC9109284.
9. Batson A, Glassman A, Federgruen A, et al. The world needs to prepare now to prevent polio resurgence post eradication. BMJ Global Health. 2022;7(12):e011485. doi: https://doi.org/10.1136/bmjgh-2022-011485
10. ID-308 – COST MINIMIZATION ANALYSIS OF THE HEXAVALENT VACCINE WITH ACELLULAR PERTUSSIS COMPONENT (HEXA PAC) VERSUS HEXAVALENT VACCINE WITH THE WHOLE CELL PERTUSSIS COMPONENT (HEXA PC). PARAGUAY 2025.Olivera Ignacio (1); Martínez Celia (2); Grau Carlos (1); Lazarov Luis (1); Dibarboure Hugo(1). Center for Economic Research, CINVE-Health, Montevideo, Uruguay; (2). Hospital de Clínicas, Asunción, Paraguay.
11. ID-307 – COST-MINIMIZATION ANALYSIS OF THE HEXAVALENT ACELLULAR PERTUSSIS COMPONENT VACCINE (HEXA PAC) VERSUS HEXAVALENT WHOLE-CELL PERTUSSIS COMPONENT (HEXA PC). URUGUAY 2025.Olivera Ignacio (1); Grau Carlos (1); Lazarov Luis (1); Dibarboure Hugo (1). Center for Economic Research, CINVE-Health, Montevideo, Uruguay.
12. WHO, Fully-funded Gavi, the Vaccine Alliance, is a lifeline for child survival, says WHO. https://www.who.int/news/item/28-03-2025-fully-funded-gavi–the-vaccine-alliance–is-a-lifeline-for-child-survival–says-who

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I believe in making it very difficult for people to refuse vaccines. There’s enough of the libertarian about me that I wouldn’t actually strap them down and inject them, but I’m fine with school districts making parents write out their conscientious objections to children being immunised or with sports clubs requiring adult proof of immunisation before people can join. What I or you think is, though, beside the point. Much of the US is walking away from cajoling and compulsion and there’s great pressure in Europe for similar change. We can either go on moaning about how we wish the world hadn’t changed or we can respond effectively.

Before the current US Administration began rewriting vaccine recommendations, one in six US parents wasn’t following them. We used to joke that vaccine-preventable diseases in the West had become diseases of children of the over-educated middle classes who shopped at Whole Foods and did naked yoga classes; vaccine refusers now are still more likely to be white, but they skew to being conservative, very religious, and young. Recommendations actually reduced uptake in this group because most have a deep distrust of the Federal Government and its agencies.

Formal vaccine refusals in Poland more than doubled from 2017 to 2022 and reached over 87,000 in 2023, a 1685% increase since 2003; measles cases surged 10x in early 2024 due to falling rates. Ireland, where I live, has the third-lowest childhood vaccine coverage rate in the OECD.

There are bright spots too, Italy for example, and the battle is far from lost. But the mistrust now endemic to the United States is coming to Europe.

High-handed US and European experts

You can understand confusion, if not mistrust. About half of parents in the USA did not vaccinate their children for flu in the past year, compared with 41 percent who said they had done so, a Washington Post / Kaiser Family Fund poll found. Coverage started declining after 2019. In 2016, the US CDC said that the nasal flu vaccine used in children provided “no measurable benefit” (injectable vaccines for adults were, as usual, highly effective). In the same year, Public Health England said that the same vaccine (produced by a British company in a British factory) was 58 percent effective. Canada followed the UK, saying that its population was very different to the USA! It’s very unlikely that both the Americans and the Canadians were right — despite those obvious population differences…. Few journalists covered the story — I suspect because no-one wanted to be accused of promoting vaccine scepticism. The vaccine is now recommended again in the USA.

Few American paediatricians and even fewer nurses would have been able to explain this to parents because no-one ever bothered to give the professionals an explanation. What do we think doctors told parents who asked why a vaccination was recommended then was not and then was again? British parents who did a web search (this was pre-Chat GPT, remember) might have asked why their children were getting an apparently ineffective vaccine and would have met equally bemused stares from their health providers. Did anyone brief social media influencers or health journalists? Of course not, who do they think they are? What impudence…

I know some of those involved and I’m sure that there was no subterfuge and nothing sinister going on; the answer is likely to be dull and involve methodology and surveillance systems.

This is the way we all used to approach treatment discussions 40 years ago — the doctor told you what to do, you thanked him (it was nearly always a him) and you did it. Questions were a sign of disrespect, of even psychological illness. I was recently treated by a Russian dentist, now practising in Ireland, who was shocked and outraged when I questioned his recommendation to use antibiotics prophylactically; if he had been Irish, he would have been completely used to it.

Nonsensical recommendations in developing countries

Vaccine hesitancy looks a bit different in France. Those least likely to have their children vaccinated tend to be more educated, high users of the internet for information and to have lower trust in health authorities. Those who refuse vaccines for themselves tend to be at the lower end of the social hierarchy with less education and fewer financial resources. Many are ​immigrants and descendants of immigrants, and residents of French overseas departments. Both are probably likely to know about the vaccines which Western experts recommend for children in the developing world, including in Francophone countries.

I remember doing a policy interview with the health minister of a large Indian state. I was trying to find out what he might pay for an effective TB vaccine. “But”, he said, “we already have a TB vaccine. Why do I need a new one?” His top civil servant was sitting behind him and frantically gesticulating to me to try to stop me explaining that the BCG vaccine, given to almost every Indian newborn, may do nothing to prevent TB infections and, at best, may make the disease less severe in some of the children who contract it. It is, though, very good at causing severe side effects. No developed economy uses it; almost every poor one does.

I’m ashamed to say that I did not explain BCG as clearly as I should have to the minister. He was the norm, not the exception, in that series of policymaker interviews: few of those making decisions about TB vaccine policy had ever been given a thorough, honest briefing about the limitations of the vaccines their expert advisers recommended. None of the parents, of course, were ever told about any of these reservations.

There might also be a case for the current practice of giving many children in Africa and Asia a vaccine that sometimes causes polio, instead of preventing it, although I doubt it. The risks of a child contracting polio from the live-attenuated oral vaccine are probably underestimated when they’re presented to politicians and policy influencers. Hardly any parents who bring their children forward for these vaccines are told about the risk or the rationale for continuing to use them, rather than the perfectly safe inactivated vaccine used throughout the rich world.

Is it any wonder that those with insight into the developing world are sceptical? The real wonder is that vaccine confidence is still so high in Africa and Asia. That probably comes from everyday encounters with the tragic consequences of infection by vaccine-preventable illnesses, an experience blessedly denied to most Americans and Europeans.

What we need to do now

The road ahead has been cleared for us. Thirty years ago, I went out with a trainee doctor at the Royal College of Surgeons in Ireland. He was upset one evening because he had been berated by his tutor for telling an older patient that she had cancer — it had been agreed with the family that she would be told that she had a “growth” to avoid upsetting her. At least she found out: King George VI of the United Kingdom sent his daughter, Princess Elizabeth, on a world tour in 1952 because neither he nor she had been told that he had lung cancer and that it was terminal. He never saw her again. These stories shock us now because honesty, realism and communication are taken for granted in what we tell patients who are ill. These principles need to be the new basis for what we tell people who are healthy and want to stay that way.

First we need a change in attitude. Whether to be immunised or not is a decision that people will take — actually, a series of decisions. We don’t need to think about whether we like the concept or not, it is the way things increasingly are. We have to get ordinary people used to making good decisions, just as they do about other life issues such as house buying or insurance or continuing education. Ordinary people are not property experts or risk analysts or trained evaluators of course offerings, but they mostly make reasonable choices. They can do the same thing with vaccines.

Then, we need to communicate much more. Vaccine producers are free to talk to the public about recommended vaccines in many countries; where they are not, they need to be allowed to. Then they need to accept their responsibility to speak often, clearly and loudly. They are the experts on the vaccines they produce and they must tell potential recipients or the parents of recipients about the benefits and disadvantages. Of course, they need to do it in an honest and balanced way. They will be more successful if they communicate in partnership with professional organisations, charities and respected consumer groups. They can be transparent: they have a commercial interest in getting people to accept vaccines but a legal responsibility to set out all the factors in deciding whether to or not. It’s like banks selling mortgages and car dealerships selling warranties.

Researchers and healthcare providers need training in communication and answering questions. They need to be much better at helping policy makers to make decisions about vaccines. Today, too few vaccines are reimbursed and many are offered only to some of those who would benefit from them. In many countries, it is still too hard to get vaccinated and even where rules have changed, practices have not — look at Poland, for example. Politicians and public officials can unleash vaccines so that they can do even more to boost productivity, growth and wealth in society.

Those same scientific and medical experts need to be much better at talking to people who are making decisions about immunisation. Research tells us clearly what helps the right decision, but too few professionals follow the evidence. The most powerful prompt to action is a trusted health professional saying, “I would like you to do this”. Setting a good example works wonders too, but too few health professionals have had all of the vaccines recommended for them.Communication can change all of this.

The vast majority of social media influencers want to give good advice and powerful motivation but no-one talks to them — after all, we want people to follow the guidelines, not think, don’t we? For example, have you seen Dr Mike Varshavski take on 20 vaccine sceptics at once? Thirty million people probably have over various platforms and he’s brilliant. Industry and professionals need to work with influencers who specialise in women’s issues, childhood, workplace effectiveness and, of course, health. Look at this from Dr Ahmed Ezzat — his videos on RSV reduced calls to the emergency services by 25% — and just think what he can do for vaccines.

Journalists are discouraged from writing pieces about vaccine decisions — “just tell people to follow expert recommendations”. Many, consequently, avoid writing about vaccines. We need to treat these journalists as powerful allies in helping lay people to make important decisions with lifelong implications for their risk of developing chronic illnesses. It’s the way that property developers treat journalists who write about houses,

Honestly, I still think it would be simpler and still ethically correct to just nudge almost everyone into getting immunised but that is not an option in many places now and, given the global market in ideas, won’t be one anywhere soon.

Parents get things right

Asia should encourage us. Many parents save and spend to get their children the best vaccines. The state often provides old tech or nothing, so middle-class parents take their children to private clinics for the best protection and pay full price for it. Of course, it’s not fair to poorer children and it is crazy public policy given that population sizes will plunge across Asia over the next 30 years so every child, whether middle class or not, is a precious national resource. Still, it shows that individual families can and do make better decisions than health policy makers when the routes of communication are open and used well.

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