Immune Imprinting and the Prevention of Spread

Kevin Kavanagh, MD

The United States Vaccine effort is starting to falter in terms of efficacy and public acceptance. On November 1, 2022, Infection Control Today^® (ICT^®) published an article questioning our current booster formulation. On December 9, 2022, a commentary published in The Journal of the American Medical Association (JAMA) Network entitled “Urgent Need for Next-Generation COVID-19 Vaccines“ also sounded the alarm.
 
The efficacy of boosters in preventing severe disease in the elderly was still high during a period that BA.4/5 predominated. A recent study published in the Centers for Disease Control and Prevention’s (CDC’s) Morbidity and Mortality Weekly Report (MMWR) explains that the new bivalent BA.5 booster has a 73% efficacy in preventing hospitalizations in those aged 65 years and older who have received a prior vaccination or monovalent booster (84% efficacy compared to unvaccinated). Those 18 and older had just a 38% efficacy in preventing hospitalizations compared to individuals who had prior vaccinations or monovalent booster. However, there was only a 2- to 5-month follow-up, which is extremely short, and further waning may occur.
 
In addition, these vaccines and boosters no longer effectively prevent the spread of SARS-CoV-2, and the prevention of spread is key to preventing long COVID-19 and future viral mutations.

This efficacy reduction is happening simultaneously as infections from variants with even more significant immune escape potential are increasing in our nation. The BQ.1, BQ1.1, XBB, and XBB.1 subvariants are resistant to monoclonal antibodies. A recent study published in Cell, stated “All clinical monoclonal antibodies were rendered inactive against these variants.” The article also stated that these variants pose a significant threat to the efficacy of the bivalent booster.
 
Even more concerning is that there may be significant immune imprinting with the mRNA vaccines.

Immune imprinting was evident in the animal data presented to the CDC’s vaccine committee. All animals were given the monovalent vaccine to the original wild-type virus. The mice were then given either a monovalent booster containing the original spike protein, the BA.1 spike protein, the BA.5 spike protein, or a bivalent booster that contained both the wild-type (original) and BA.5 spike protein. Surprisingly, the immune response to the original wild-type virus from the BA.5 monovalent booster was essentially the same as that elicited by the original monovalent booster. And the elicited BA.5 booster response to the wild-type virus was larger than that to the BA.5 variant. Thus, immune imprinting may be taking place where the maximal boost in response is to the original virus one is exposed to. This concern is supported by the research of Roltgen K et al, which found that “Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens.” Prior infections have also been observed to cause imprinting. Reynolds et al, found that “Omicron infection after previous Wuhan Hu-1 infection failed to boost neutralizing antibody and T cell responses against Omicron, revealing a profound imprinting effect and explaining why frequent reinfections occur.”

This finding received far too little attention and foretold the findings in research papers reporting only marginal if any, increased benefit of the bivalent booster over the original booster.

Questions Linger
 
For children, we must ask, do we want to continue to imprint them with the original variant? Or would it be better to use a bivalent or monovalent version of the vaccine targeting a recent variant?
 
Should Pfizer & Moderna discard much of their old stock and reformulate their vaccine? For mRNA, pharmaceutical companies appear to be making billions from vaccine sales. Should they immediately reformulate whenever a new dominant variant arises? This may well be a 3- to 4-month cycle. This, of course, would be a stopgap measure. Reformulation of variant-specific vaccines when variants are arising at such a rapid rate is not a long-term strategy.

Prevention of spread is of utmost importance. With the dangers of long COVID-19 and the mounting deaths (potentially almost doubling the total from acute COVID-19) and disability from this disease, we must set our goal at the prevention of spread. This pandemic is damaging the cardiovascular and central nervous systems of far too many individuals. The latter is causing brain fog, memory, and what I like to call COVID-19 Personality Disorder. Yes, infections through environmental stresses and physical brain damage can change one’s personality.
 
Immune dysfunction from COVID-19 is another concern, as evidenced by the overwhelming number of RSV hospitalizations. This occurred even though, at the beginning of December, we had more RSV cases in 2021 than we had in 2022.

The best hope of blocking transmission is with mucosal vaccines. The current mRNA vaccines do not produce a robust IgA mucosal response and, thus, have low efficacy in preventing infections and spread.

We need a warp speed on new vaccine development. Why this is not being done is one of the most significant failings of our pandemic response. Until we have a vaccine that stops spread, we need to use N95 masks, avoid crowded indoor venues, and markedly increase indoor ventilation and air sanitization (with upper room UV-C units).
 
Immediate action is needed; one should strongly consider the following:
1. Administering a bivalent or monovalent BA.5 (or current variant) vaccine to COVID-19-naive individuals, especially young children.
2. Administering a monovalent BA.5 (or latest variant) booster to those previously vaccinated or infected with COVID-19.
3. Vaccine reformulation upon each emergent wave of the virus is a stopgap measure, but it must be implemented to the best extent possible.
4. Funding a new Warp Speed initiative designed to develop mucosal vaccines.
5. And, of course, the use of N95 masks and increasing indoor ventilation, along with the help of upper room UV-C, is of utmost importance.
 
But above all, we need to incorporate the new data we have gathered and lessons we have learned to create a more effective strategy in our approach to COVID-19.