At Last, A Scientific Explanation of Vaccines in the Time of COVID

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Dr. Fauci, speaking on vaccinations: “Past unsuccessful attempts to elicit solid protection against mucosal respiratory viruses [COVID-19] and to control the deadly outbreaks and pandemics they cause," he said, "have been a scientific and public health failure that must be urgently addressed.” That's a lot to unpack.

Dr. Anthony Fauci, along with two of his colleagues at the National Institute of Allergy and Infectious Diseases, has written a long, science-filled piece on the hurdles of creating a vaccine against some viruses, particularly COVID-19. Their explanations of our immune response help us to disentangle and understand the public health failure and triumph of the COVID-19 viruses.

COVID-19 displaced influenza as the “deadliest vaccine-preventable viral respiratory disease.” Despite 60 years of research development, the annual influenza vaccine has a limited clinical utility, effective 15-60% of the time in reducing the risk of “severe disease, hospitalization, and death.” And with limited elicited immunity, vaccines must be reformulated and given annually.

For many of us, our understanding of respiratory virus vaccines involves measles, mumps, and rubella (MMR) – where vaccination is “one and done." But as the authors point out, these viruses differ from influenza and COVID in three clinically relevant ways.

  • Measles, mumps, and rubella all replicate in the mucosa, the lining of our respiratory tract, but then they enter the bloodstream, and those infectious virions (particles) come in contact with many different components of our immune response.
  • Their long incubation period allows for the “full force of adaptive immunity.” As a reminder, adaptive immunity brings on antibodies, as well as T cells. It is the immunity that has memory.
  • The synergy of these two factors results in essentially lifetime immunity.

COVID-19 and company, including respiratory syncytial virus (RSV), stay local and replicate quickly, evading adaptive immunity's full force and not being exposed to a broader range of immune sensors. This is not the case for infectious virions associated with MMR as they become bloodborne(viremia). The presence of viral mRNA in the blood with COVID differs from viremia, if is not infectious and offers no specific binding sites. 

COVID-19 is a non-systemic replicating virus (NSRV) and, like influenza, will repeatedly infect individuals without “ever eliciting complete and durable protection.” Moreover, the mutation rate of COVID-19, like influenza, results in rapid antigenic drift – another way of describing the underlying mechanism for the different variants of concern. As with influenza, a universal COVID vaccine is a tough ask. 

“Taking all of these factors into account, it is not surprising that none of the predominantly mucosal respiratory viruses have ever been effectively controlled by vaccines.”

The authors provide six key points.

  • Human immune responses may not fully control natural infections with mucosal respiratory viruses [NSRVs]

The respiratory and digestive tracts are the wide-open gateway for pathogens to infect us. Once inhaled or ingested, the immune system needs to identify the “foreign” to distinguish frenemy from enemy and tolerate or attack and kill. The immune system may choose the middle way and down-regulate its response to prevent collateral tissue damage, as we learned about in discussing cytokine storm in cases of severe COVID-19.

We have co-evolved with COVID-19, as witnessed by its diminishing severity of illness. NSRVs have developed ways to evade our adaptive immune response, just as we have down-regulated our immune response to lessen the collateral damage to our organs. As the authors write, there is a “Faustian bargain” between tolerance of “low or intermediate pathogenicity” and the all-out “destructive forces of an immune elimination response.” Immunotolerance is more a feature of the upper respiratory tracts where COVID-19 is at work, then deeper in the respiratory tree (think lungs) where immunologic warfare to control infection is necessary.

  • Since mucosal and systemic immunity only partially protects against infection … we must take advantage of alternative host immune mechanisms

COVID-19 begins infecting us in our upper respiratory tract where local mucosa-associated lymphoid tissue (MALT) secretes IgA, the prime immune combatant when an infectious invader is detected. While there will be a systemic response involving circulating antibodies and T and B cells, that response is muted because the mucosa does not send a “strong” signal to these immune components. The movement of IgA from plasma cells to the area of infection, a process termed transudation, is not “fully understood.” We do not know “how to elicit and sustain such high antibody levels [of IgA] with vaccination.”  

One of the hallmarks of severe COVID was the spread of infection deeper into the respiratory tract, causing pneumonia. As it turns out, the lung has its own deployed immune resources and acts “semi-autonomously” so that a vaccine to promote mucosal immunity may not provide pneumonic protection.

  • Immune correlates of protection against mucosal respiratory viruses are incompletely understood… and exhibit inter-individual variation.

Serum antibody titers are one indirect biomarker of our immune response; our immune system is too complex for one measure to be fully expressive of its efficacy or deficiency. At a minimum, we need to know which viral epitopes (the binding site of an antibody) are being impacted. The mRNA vaccines were targeted at the spike epitope of COVID-19. Part of the value conferred by infection-acquired immunity was the variation in epitopes that were targeted.

“…correlations between serum antibody titers and susceptibility to influenza infection may be statistically valid in large studies, but imperfect in the context of individual variation, rapid viral evolution, and waning titers.”

We may have to decide how much control we can exert with a vaccine. For these NSRVs, total prevention is probably not “in the cards,” and we may have to settle for a reduction in disease severity, as we have with influenza vaccines.

  • Vaccine-related questions of the route of administration, antigen configuration, [and] adjunctive therapy are of great importance for current research

Those two gateways to infection, our lungs and gut, are lined with 30-40 square feet of mucosa, almost all with underlying lymphoid tissue secreting IgA [1]. Mucosal immunization -- think nasal vaccination rather than an injection -- seems to be a more optimal means of heightening our immune response to respiratory viruses. And as previously mentioned, the target epitope(s) make a difference. Targeting “conserved” epitopes – those showing relatively little change, like COVID-19 spike protein is easier. But these conserved epitopes may not provide the breadth of protection we have seen with individuals immunized with vaccination and infection. Also, in some cases, conserved epitopes have not been highly immunogenic.

Our immune experience also plays a role. Those of us exposed to many pathogens have a broader range of immune tools – exposure to other pathogens can create “cross-reactive immunity based on shared epitopes on related viruses and viral strains.” In some situations, it is true, what doesn’t kill you, makes you stronger.

“Although such conserved epitopes seem ideal candidates, vaccines based on this approach have not been particularly successful.”

  • Vaccinated hosts and host risk groups are many and heterogeneous

For a disease that impacts some groups more than others, subjecting the entire population to immunologic nudges may not be the best precision medicine. Increasingly, one size does not-fit-all.

“It is inevitable that various human risk groups may require different vaccines or vaccine formulations.”


The authors go on to suggest that the frail and elderly are the canaries in this particular coal mine. Because of their diminished response to vaccination and greater risk of severe or fatal disease, “factors that make successful vaccination of older people a benchmark for other groups.” 

  • Public health considerations … must contribute to shaping vaccine design…and public acceptance.

The public health messaging around COVID-19 vaccines was abysmal – overpromising and underdelivering in terms of the degree and timeframe of protection and the subsequent need for boosters as COVID-19 morphed into other variants of concern. Now that the emergency of the pandemic seems to be in our past, future vaccine development, including its target patients, mode, and frequency of administration, needs to be developed, taking into account the needs of patients, providers, and regulators.  

This article has a chameleon-like quality. For those on the political right, this may be, as social media has suggested, Fauci coming clean, admitting that the COVID-19 vaccines do not work. For those on the political left, it may be a moment of hubris, recognizing how little we actually know; we are not masters of our bodies, let alone the universe. I have tried to be a fair translator of this science-filled seven-page article to help separate science from science fiction.


[1] IgA compromises 65-70% of our human immunoglobulins to give you a sense of how large a defensive network our lungs and gut create.

Source: Rethinking next-generation vaccines for coronaviruses, influenza viruses, and other respiratory viruses Cell Host & Microbe DOI: 10.1016/j.chom.2022.11.016