Don't compare drugs to vaccines!

Let’s throw out the dirty bathwater, but let’s not throw out the baby with it!

As much as I understand RFK Jr’s intentions to reform the entire vaccine landscape, I continue to caution against potential fundamental errors the new healthcare officials might make. There is no doubt that despite all modern vaccine technologies and the extensive knowledge that has developed around them, vaccinology remains a highly empirical science. Any vaccinologist would have to admit that testing and developing a new vaccine is ultimately, to a large extent, a matter of trial and error. It may therefore be wise, indeed, to re-examine and analyze, using today’s knowledge and methodologies, the data underlying a whole series of vaccines that were eventually approved for the market in this way.

The question, however, is why vaccines have historically been assessed differently from drugs for marketing authorization. It is indeed true that vaccines cannot simply be compared with medicines/ drugs for several reasons:

Drugs work directly on the body or pathogens. For example, antibiotics kill bacteria or stop their growth, while antiviral drugs inhibit viral replication. Drugs can act on various cells, organs, or systems within the body to control or cure a disease. The effect of drugs or medicines depends on their concentration in the body, particularly at the site of action.

Vaccines, however, work by teaching the immune system to recognize the pathogen. This primes the body to mount a rapid and protective immune response if exposed to the actual disease in the future. Essentially, vaccines rely entirely on the immune system’s response, functioning by educating the immune system to recognize and fight, rather than directly combatting the pathogen themselves. They are often called ‘biologicals’ because they’re derived from biological materials or resources and harness the body’s natural defenses for protection. The effect of the vaccine, therefore, depends much more on the type of immune response it induces rather than on the concentration of the vaccine’s active ingredient(s). The nature of the immune response largely depends on the type of antigen used in the vaccine. Hence, the saying that ‘a vaccine is only as good as its antigen’, the final selection, formulation and delivery of which are largely based on empirical data.

If the vaccine elicits neutralizing antibodies and is used prophylactically, its protective effect may correlate with the concentration/titers of the antibodies (Abs) produced (e.g., in cases of acute self-limiting infections/diseases). However, when no such correlate of protection exists, only empirical preclinical and clinical studies can determine whether the vaccine provides protective immunity in vivo without causing immune pathology or serious inflammatory reactions. This empirical approach is partly what underlies the lengthy research and development pathway for vaccines.

While drugs can indirectly affect the immune system, they often act directly on pathogens or symptoms, rather than relying on the immune system itself. In many cases, their effectiveness and safety in a given individual or patient can be readily assessed by determining their concentration in the blood or target organs.

In the case of acute, self-limiting infections, however, vaccines can contribute not only to individual protection but also to the protection of an entire population, provided they help maintain herd immunity.

Ignoring the contribution of childhood vaccines, particularly of live attenuated vaccines(LAVs) to herd immunity against certain acute, self-limiting infections is a major shortcoming in the reasoning of those who believe that the risk-benefit analysis of these vaccines should be solely based on comparing disease prevalence in vaccinated versus unvaccinated children through randomized, double-blind, placebo-controlled studies.

These studies measure the cumulative health effects of vaccines on healthy individuals outside of an epidemic. In regions or during seasons where exposure to the virus is low enough to substantially reduce the chance of productive infection, the protective effect of the vaccine (i.e., against the target disease) will likely be offset by vaccine-associated side effects, particularly in the case of LAVs. However, in regions where the virus is endemic, large-scale vaccination programs among immunologically naïve individuals can significantly curtail viral transmission, thereby avoiding productive infections among previously infection-primed individuals with declining neutralizing Ab titers, as well as among individuals who are neither infection- nor vaccine-primed. This already explains why the cost-benefit analysis of childhood vaccines against acute, self-limiting viral infections (ASLVIs such as measles, mumps and rubella) should ideally include long-term monitoring of large-scale, placebo-controlled vaccine efficacy studies in endemic regions where viral outbreaks occur depending on societal or seasonal factors, as the dilutive effect of vaccine-associated side effects on the protective impact of the vaccine will be much less pronounced compared to regions where the virus is not endemic.

However, conducting double-blind, placebo-controlled studies in endemic regions to account for viral exposure during an epidemic would be unethical. This is especially true for the types of infections these vaccines aim to protect against (i.e., ASLVIs), as protection against these infections correlates with pre-existing infection- or vaccine-primed neutralizing Abs. Since conducting placebo-controlled clinical studies in populations at high exposure risk with vaccines that induce Abs known to correlate with protection is unethical, it is impossible to test the risk-benefit ratio of these childhood vaccines under conditions that would allow us to prove their primary benefit—namely, maintaining herd immunity and thereby preventing epidemics from causing casualties across the entire population.

Highlighting the health-adverse effects of LAVs while ignoring their contribution to maintaining herd immunity is like emphasizing the impoverishing effect of paying taxes while ignoring their role in preserving and maintaining public goods and services.

This being said, I’ve already highlighted in a previous contribution (It often takes scientists an incredibly long time to understand things that are pretty obvious with simple common sense...) that there is still much room for the design and development of alternative immune interventions to maintain herd immunity in populations without the need to use LAVs.

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