The Technological Marvel of Combination Vaccines

Horrifying. –editor’s note

— Many questions remain for co-formulating COVID vaccines, but pursuing this now is the right move

Two white rubber gloved hands pour yellow and blue liquids from beakers into another vessel.

In recent days, Novavax and Moderna have announced the development of combination vaccines that would protect not only against COVID-19, but also against influenza. In the case of Moderna, they are testing a combination vaccine that also includes protection against respiratory syncytial virus (RSV) — a viral illness for which no vaccine is currently available. Such combination vaccines would be a major advancement. Because COVID-19 vaccines can be administered simultaneously with other vaccines, albeit in separate injections, it is no surprise that the next step is to co-formulate them in the same injection with other vaccinations.

What Makes Combination Vaccines So Valuable?

Combination vaccines are extremely valuable for several reasons, chief among them is convenience. If, during one visit to a provider, a person can get multiple vaccinations, it ensures uptake of all those vaccines without the need to schedule multiple visits or use multiple injections. A single needle puncture is better than multiple punctures, even for those who are not needle phobic. As more vaccines are developed, combination vaccines become critical in getting doses into arms with the minimum number of injections.

Combination vaccines are not a novel ideal. In fact, combination vaccines are the mainstay of routine vaccination. Children today receive several combination vaccinations including the well-known MMR (measles, mumps, rubella) and DTap (diphtheria, tetanus, acellular pertussis). These types of vaccines have a long history with DTP, the first combination vaccine used in humans, dating to the 1940s. Pentacel immunizes against five different pathogens at once. Such convenience, especially with hard-to-reach populations, is invaluable. Adults also receive combination vaccinations, most prominently the Tdap (tetanus, diphtheria, acellular pertussis) boosters. Many physicians, including myself, wish there were more combination vaccination products available because they have the potential to significantly increase vaccination rates.

Safety and Efficacy

It is, of course, necessary to make sure that combination vaccines are as comparatively safe and efficacious as their individual counterparts. Because more antigen is present in a combination vaccine, injection site reactions might be more pronounced, fever might be slightly higher, and tolerability lower. For example, the four-target vaccine MMRV (measles, mumps, rubella, varicella) is not used for the first immunization against these pathogens. Because of a higher rate of febrile seizures, babies of about 15 months of age are given the varicella component separately. However, around age 5, the MMRV is used because this side effect is no longer a medical concern.

It is also important to establish that the separate components of a combination vaccine do not interfere with each other or blunt the immune response. This immune interference was a concern with vaccines combining Hib with DTap. For instance, vaccines with different storage conditions or delivery mechanisms (e.g., subcutaneous vs. intra-muscular; lipid nanoparticle encased) may not be the best candidates to combine. It is also important to combine vaccines that have compatible age or time-based schedules for administration.

As scientists explore a combination flu and COVID-19 vaccine, they will be looking closely at all of these safety and efficacy considerations, and countless others.

Combination Vaccines and the Anti-Vaccine Movement

It’s important to emphasize, considering widespread disinformation from the anti-vaccine movement, that there is no “antigen overload” risk with combination vaccines. The human immune system is bombarded with antigens every day. We even become bacteremic, when we brush our teeth, or eat. The antigens contained in a combination vaccine are miniscule by comparison. The first vaccine ever created, against smallpox, was notoriously laden with all sorts of particles and impurities but was incredibly efficacious and led to control and eventual elimination of one of humanity’s deadliest scourges.

In the present environment, we’re likely to see individual attacks on COVID-19 combination vaccines long before they are available. We’ve previously seen such attacks on the MMR vaccine — these attacks became so pervasive that manufactures started to produce the single vaccines again to placate those who were the victims of a concerted disinformation campaign. But we can learn from these past challenges. It will be important to fight disinformation about the COVID-19 combination vaccines early on, and encourage their uptake when they become available.

The Future of COVID-19 Vaccination

At this stage there are many unanswered questions about COVID-19 vaccination. What might a potential booster schedule look like? Will strain changes eventually be needed in response to variants? Will COVID-19 vaccination transition to a routine childhood vaccination? These questions are only the top of the iceberg. But one thing is certain: we should aim to make COVID-19 vaccination convenient, normal, and easy. Proactively working on next generation vaccines that do this by combining with other vaccinations, altering the mode of delivery (e.g., oral or nasal vaccines), or simplifying storage requirements are important tasks. And it’s encouraging that we’re pursuing this now. Vaccines are technological marvels, more valuable and important than the newest iPhone, and continually improving them will benefit us all.

Amesh Adalja, MD, is a senior scholar at the Johns Hopkins Center for Health Security, an adjunct assistant professor at the Johns Hopkins Bloomberg School of Public Health, and an affiliate of the Johns Hopkins Center for Global Health.


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