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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We looked around, found nothing, and shortly went back to sleep.

In the morning, my wife was opening our interior shutters, which are used to keep out sunlight, when she discovered… a bat.

What happened next seemed perfectly sensible at the time. I went to the garage, got a heavy leather glove, returned, and grabbed the bat while my wife opened the front door. We stepped outside, let it go, and it flew away. We were glad to have it out of the house and proceeded to fix breakfast.

I had just made two mistakes but did not realize it.

It was early August, and we had been staying at our vacation home in Kent County, Maryland, on the Eastern Shore. In a few days, we were back home in our retirement community just outside Baltimore. We have a lady who watches out for our vacation place when we are away. I asked her to arrange a pest control person to check out the house to see if there were other bats, perhaps in the attic. As it turned out, he arrived when we were back just before Labor Day to celebrate our 63rd anniversary.

We described what happened. He looked at me and said, “You really should go to the emergency room or see a doctor.”

My wife smiled and said, “He’s a doctor.”

“Well,” he replied, “I just want you to be safe.”

He looked around the entire house and found multiple places where a bat could slip in. He found a few bat droppings in the attic. Still, he thought this was probably a “one off.” Maybe the bat got in when the garage door was open or something like that. He said he would send us a proposal for caulking up the various holes he found. We were back home in Baltimore when we got a message from our property manager that he had sent his proposal, but he also said he really thought I should go to the emergency room. Up to now I had not paid much attention but having heard it multiple times, I decided to do some research.

What I learned

I turned to Open Evidence, an AI system that looks only at quality medical and scientific information. The answer was unambiguous. I should go to the emergency room, now.

Because the bat had actually been crawling on my head while I was asleep, and because it was no longer available for testing, I should receive rabies post-exposure prophylaxis (PEP.)

Bat bites can be so small that a person may never see or feel them. And rabies presents an unusual medical calculation: The probability that this particular bat was rabid and infected me was exceedingly small, but the consequence of being wrong was enormous. Once clinical rabies develops, it is fatal; there is no treatment. But PEP given before symptoms begin, is nearly 100% effective.

That was a clear wake up call.

The current guidance supports the central lesson. CDC says potential direct physical contact with a bat warrants assessment, and Maryland specifically advises considering treatment when bat exposure cannot reasonably be ruled out. CDC also advises not releasing a bat found in the home until public-health experts have been consulted, because testing the bat may determine whether PEP is necessary. Guidelines favor treatment whenever exposure cannot be excluded.

The last sentence is the key one.

Just to be clear, it is very uncommon for a person to develop rabies from a bat. In our area, less than 1% of bats are infected. I had no clear bite or scratch. The risk in my case was extremely small. The problem is if I do win the Lottery, that’s bad.

Bats are the source of most rabies cases, but these are rare. There were two deaths from rabies (neither person received PEP) in America last year but over 30,000 people were potentially exposed and received PEP.

The rabies virus travels from the bite site through peripheral nerves toward the spinal cord and brain. Once symptoms appear, the disease progresses to severe neurologic illness ending in coma and death. There is no reliably effective treatment once clinical rabies has developed. The opportunity to prevent the disease is therefore before symptoms begin.

What to do if you encounter a bat

I had not thought about rabies since I took the board certification exam in infectious diseases some 40 years ago. I worked with cancer patients, not the general population, so I had no experience other than book learning long ago.

It did not occur to me that the bat could have been rabid or that it might have bitten me, since I did not find evidence of a bite or scratch, nor was the bat aggressive. Not being worried about rabies, I did not think to kill the bat so it could be tested. Absent that testing, as I learned, I needed rabies post exposure prophylaxis or PEP.

I was talking with a speech therapist whose family had a cabin with “lots of bats flying around all the time.” She remembered as a kid being told that if you got bitten by a rabid bat or other animal, they would “inject you with 9-inch needles into your abdomen many, many times with lots of side effects.“ She wasn’t entirely wrong. The nine-inch needles were folklore, but the old rabies treatment really did involve numerous injections into the abdominal wall. The earliest vaccines descended from Pasteur’s 1885 work and were prepared from rabies-infected nervous tissue. They were far more cumbersome and produced substantially more adverse effects than today’s purified cell-culture vaccines.

Fortunately, that era of painful shots is long gone, but it was only in 1980 that the modern anti-rabies vaccine was licensed, so it is no surprise that the myth still abounds.

None of this means that bats are bad animals. Quite the contrary. Bats have been saddled with centuries of bad publicity, from witches to Dracula, when in reality they are among our most useful neighbors, gobbling huge quantities of insects like mosquitoes every night.

That said, the CDC reports that rabies exposures have recently increased. We just read that a rabid bat was found in a school about 20 miles from our home, and rabid bats have been reported in Los Angeles recently.

Post-exposure prophylaxis

My primary care physician called the local emergency room to determine if they had the PEP available, and learning that they did, and that they were “not too busy,” we headed off.

After signing in (“oh you’re here because of rabies”) we were ushered into the triage room where a doctor and nurse took a history. The doctor, obviously very experienced, said that there was no question that I needed PEP. He then looked at my wife and said, “You were asleep in the bed next to him, so the bat may have crawled on your head also.” “I have hair on my head,” she responded. “Yes, but he could have walked across your forehead, and you might not have been aware. You need PEP also.”

PEP for someone who has never previously been vaccinated against rabies consists of human rabies hyperimmune globulin, which supplies immediate antibodies, followed by four doses of rabies vaccine given on days 0, 3, 7, and 14 to give long lasting protection.

We went back to the waiting room and after a while we were ushered into the main area of the ER. They had to order PEP from the pharmacy, which took a while until it arrived. The hyper immune globulin dose is based on weight. For me it was 2.6ml and for my wife it was 1.7. If there had been evidence of a bite, some of the globulin would have been injected there. But for us it was divided into two shots, one into each thigh. And then the vaccine, 1ml, goes into the shoulder.

We now are back three days later for the second vaccine dose. We will still have day seven and fourteen to go.

I told this story to retired senior engineer who said she had grown up on a farm and would have done exactly the same thing with the bat. We had lunch with a family medicine physician; he also was not surprised that we just got rid of the bat. That made me feel better because, as is always easy in retrospect, it was not smart to try and catch the bat myself. But given that I did, I should have killed it so it could be checked for rabies. Chances are it would have been negative, and we would have escaped getting PEP.

But even more importantly, it never occurred to me that the bat might have bitten or scratched me on the head since I did not see any obvious evidence. I really should have been curious and looked up the proper course of action right away. Fortunately, the pest-control man knew enough to keep pestering us. Eventually, I listened.

So here is the lesson I would pass along. If you have direct contact with a bat (or other wild animal), don’t handle it yourself. Contact animal control or your health department so that it can be safely captured and, when appropriate, tested. If the animal is gone and can’t be tested promptly, seek medical advice about whether rabies prophylaxis is needed. Rabies is exceedingly uncommon. But this is one of those unusual situations in medicine where a very small probability is paired with an almost unimaginable consequence.

And should you need the shots, don’t worry about those childhood stories of enormous needles in the belly. Modern rabies prophylaxis is nothing like that. It is still a pain in the butt — although, in our case, mostly a pain in the thigh.

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It typically begins with the sudden onset of fever, chills, headache, and body aches. It then progresses to cause sore throat, cough, and nasal congestion. Redness of the eyes, abdominal pain, vomiting, and diarrhea can also be associated with influenza.

Influenza is spread from person to person by respiratory droplets created by coughing or sneezing. Contact with respiratory droplet-contaminated surfaces is another mode of transmission. Such surfaces include door knobs, elevator buttons, computer keyboards, and mobile devices like tablets and smartphones. Outbreaks of influenza typically begin in school aged children. This can then lead to transmission to adults, the elderly, and other children within the family.

Although the majority of children with influenza recover after about 7 days, some children even without prior medical problems can suffer serious adverse effects. Like all viral infections, influenza can weaken the immune system and make one susceptible to bacterial infections such as streptococcus and staphylococcus. These bacteria can cause co-infections such as pneumonia and sepsis — a serious sometimes life threatening bacterial infection of the blood.

Influenza can also invade the tissues of the heart and cause a dangerous condition myocarditis. Finally, neurologic complications from influenza can range from febrile seizures to viral infections of the brain called encephalopathy, which can lead to permanent cognitive impairment.

Some are at higher risk for serious complications

While these adverse effects can affect anyone, certain groups are at higher risk from serious complications of influenza than others.These include children under the age of 5 but especially younger than 2 years of age, pregnant women, adults over the age of 65, and those with chronic conditions like asthma, diabetes, heart problems, neurologic issues, or any major health condition.

Prevention is key

The best preventative measure to fight against influenza and its possible complications is vaccination with the annual flu vaccine. Flu season typically begins in October and November and peaks in January. It takes about 2 weeks for the body to generate a protective immune response after vaccination, so the time for vaccination is now. The flu vaccine is recommended for everyone 6 months of age or older but especially for those who fit the higher risk categories that were just mentioned above.

Children under 9 years of age who have never received a flu shot may need two doses usually given 4 weeks apart. There are specialized versions of the flu vaccine that are meant to be given to those who are 65 years of age or older. The flu vaccine is safe and has been shown to reduce influenza illness, doctor’s visits, trips to the emergency room, and missed work due to flu. The benefits affect all ages.

A recent study showed that flu vaccine reduced children’s risk of flu related pediatric ICU admissions by 74% during the flu seasons of 2010–2012. Another study showed that people 50 years of age and older who received the vaccine reduced their risk of flu-related hospitalization by 57%. Finally, other studies have shown that administering the flu vaccine to pregnant women (at any stage of pregnancy) can not only be beneficial to them, but it can also reduce the infant’s risk of getting the flu for several months after birth.

A common misconception about the flu vaccine is the thought that receiving the vaccine itself can cause the flu.

This is simply not true. The vaccine is compiled using an inactivated (dead) virus, so it is not possible to contract influenza from the vaccine. The live, intranasal version of the flu vaccine has not been recommended this year by the Center for Disease Control and Prevention due to its general lack of effectiveness noted during the last 3 flu seasons.

Some possible side effects from the flu vaccine include tenderness and pain from the injection site, headache, muscle aches, and chills. Fever can occur within 24 hours in 10% — 35% of children under the age of 2, but this rarely occurs in older children or adults. Generally speaking, side effects from the flu vaccine resolve within a few days.

Despite the safe and effective nature of the flu vaccine, there are a few contraindications to receiving it. As with all vaccines, if there has been a history of a severe allergic reaction — also known as an anaphylactic reaction — associated with flu vaccine, it should be avoided. Also if one has contracted the neurologic disease Guillain-Barre syndrome within 6 weeks of receiving a prior flu vaccine, one should not be vaccinated. Allergy to eggs used to be a contraindication to receiving flu vaccine, but that disqualifier has been removed recently. People with milder reactions like hives can receive the flu vaccine wherever it is available. Those with more severe reactions to eggs may need to receive the vaccine under the guidance of an allergist.

Tamiflu helps but can not cure

While the influenza vaccine is the most effective preventative measure to fight the flu, there are medications available that can shorten the course of the illness if one unfortunately becomes infected with the flu. Tamiflu (oseltamivir) remains an effective antiviral medication to treat people with influenza as young as 2 weeks of age. Another antiviral Relenza (zanamivir) is an inhaled medication that can be given to patients as young as 7 years of age. Administering these antivirals within 48 hours of symptoms can help to reduce the duration of fever and symptoms of influenza. They can also reduce the rate of severe complications especially in high risk patients.

Wash your hands

There are other preventative measures that can help one stay healthy during flu season.Frequent hand washing can help to limit exposure to germs. If soap and water are not nearby, alcohol based hand sanitizers (Purell) can be used. Avoiding close contact with those who are visibly sick can help reduce the risk of becoming sick. At the same time, staying home from work or school when you are sick can help prevent the spread of illness to other people. Covering your nose and mouth with a tissue while coughing or sneezing (or coughing/sneezing into your elbow) can also prevent those around you from becoming ill.

Also, while it can be difficult as it is second nature for a lot of us, avoid touching your eyes, nose, and mouth if possible. Germs are spread when someone touches a contaminated surface and then proceeds to touch his or her nose, eyes, or mouth. Disinfecting frequently touched surfaces at work or at schools such as keyboards, desks, and doorknobs can also be helpful. You may also want to think twice about touching another person’s tablet or smartphone who is visibly ill. As always, an ounce of prevention is worth a pound of cure. Staying active, getting sufficient rest, managing stress, drinking plenty of fluids, and making healthy diet choices can go a long way to ensuring a healthy and hearty holiday season.

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