What happens if Israel fails the stress test?
Israel got an early start on vaccinating its population and began offering a third dose of mRNA vaccine in July to the older age group (≥ 60 years). The results from an observational study comparing the clinical outcome of participants who received a third shot to those in the same age group who had received only two shots over the same period clearly indicated that the risk of severe disease dropped by a factor of almost 20. Additionally, those who received the third dose were also enjoying some level of protection against infection as they were also less likely to test positive for SARS-CoV-2 (1).
These are strong results, and at first glance many of those within this age group and not yet boosted might feel ashamed for their indifference in protecting themselves and others! However, there is a catch, and it’s not about potential biases in the analysis of the study results, or criticism from a public health perspective of delivering additional shots to individuals while many others have not even had their first.
The caveat is much more fundamental and has to do with immunology: a discipline that seems to have been largely reduced since the crisis began to measuring antibodies (Abs) in the blood. The results above were obtained after a very short observation period (12 days), and there is no data yet on the long-term outcome of repeated booster immunizations. This prompts an interesting question: could the immune-protective effect observed within 2 weeks of a booster injection trigger a short-term replenishment of the ‘lost’ protection against infection while at the same time not translating into long-term protection against infection or disease? The answer is most definitely ‘yes’ and can only be understood if one brings into play the single most important confounder of all Covid-19 vaccine efficacy studies conducted thus far: innate immunity. It is well known that, regardless of any induced antigen (Ag)-specific adaptive immune response, all vaccines (including mRNA vaccines) have an adjuvant effect: they stimulate innate immune effectors, some of which have antiviral activity and/or facilitate adaptive immunity (2, 3, 4). Without going into mechanistic detail, there is no doubt that some of these innate, nonAg-specific immune responses have a short-lived antiviral effect. This could already explain why booster doses in the population described above can prevent viral infection while recalling anti-spike Abs. It may also be tempting to assume that these recalled Abs are now responsible for enhanced protection from both infection and disease. However, from an immunological viewpoint, it is difficult to understand how a rapid recall of the very same anti-S Abs in a previously vaccine-primed population would now all of a sudden enable better protection from infection and disease. If innate immunity is indeed the confounder, then the outcome of long-term surveillance studies would look very different. Given the more potent neutralizing Abs booster shots are generating against variants (5), the S(pike)-directed immune pressure in the population will only continue to rise while still failing to curtail the spread of the predominantly circulating highly infectious SARS-CoV-2 variant (e.g., Delta variant). On the contrary, it would be reasonable to assume that upon an additional booster shot the more potent Abs further contribute to selecting S-directed immune escape variants and, therefore, turn the previously primed population in an even more fertile breeding ground for the highly infectious Delta variant. As vaccine-elicited Ab responses have a much longer duration (and can be memorized) than that induced by short-term innate immune activation, and as vaccinal Abs suppress the functional capacity of pre-existing CoV-reactive innate Abs, short-term vaccine-mediated innate immune protection against viral infection or disease does not automatically imply a positive effect of the vaccine on viral infection or morbidity rates in the longer term. Interpretations from scientists who only conduct short-term surveillance studies in vaccinees, the majority of whom are adults or elderly, lead to erroneous, although peer-reviewed conclusions such as: ‘Although vaccines are less effective against asymptomatic disease (*) or against transmission than against severe disease, even in populations with fairly high vaccination rates the unvaccinated are still the major drivers of transmission and are themselves at the highest risk of serious disease’ (6). This clearly illustrates their lack of understanding of the contribution of innate immunity in providing short-term protection after vaccination, and in the more durable protection of young and healthy unvaccinated age groups.
Based on all of the above, it is reasonable to expect booster injections to only enable the virus to more rapidly evolve resistance to the vaccines. This evolution would be dramatically expedited by vaccinating and boosting more and more younger age groups. More potent anti-S Abs induced by additional booster injections will further erode their innate Ab-mediated immunity and accelerate the pace at which SARS-CoV-2 evolves from more infectious variants into variants that increasingly escape from neutralizing anti-S Abs. The single earliest and most potent indicator for such an unfortunate evolution would be a failure of the infection rate to drop below a relatively high baseline level. A peak of cases that tails off at a fairly elevated baseline level of viral infectivity in the population would reflect the diminished sterilizing immune capacity of the unvaccinated population. It is reasonable to assume that when the booster-mediated, nonAg-specific innate immune activation wanes, the vaccinees will resume their breeding of more infectious variants (e.g., Delta variant) and become more susceptible to Covid-19 disease. At the same time, the resulting growth in infectious pressure would also increase the likelihood for unvaccinated, previously asymptomatically infected individuals to become more rapidly re-exposed to the virus. This would contribute to a further rise of the infection rate in the population and, therefore, also augment the susceptibility of the unvaccinated to Covid-19 disease.
Israel’s top virologist, Dr Rivka Abulafia-Lapid, is convinced that the booster will keep existing variants under control and prevent the spread of other variants for around 6 to 8 months. She believes that Israel is currently witnessing the end of the fourth surge as a result of 3 million people taking a booster (7). A more thorough understanding of the interplay between the virus and host immunity at a population level clearly predicts, however, that the infection rate will not only halt its decrease but will also tail off at a level that is much higher than previously seen before while preparing for the next large surge in cases (see graph below). More specifically, Israel’s booster efforts are likely to generate a spectacular surge of morbidity and mortality rates in the population as a combined result of increased S-directed immune selection pressure in vaccinees (i.e., optimizing the breeding ground for the Delta variant) and enhanced infectivity rates in the unvaccinated. From a scientific viewpoint it is, therefore, difficult to understand how booster immunizations using vaccines which are not evolution-proof could prevent a highly mutable virus from escaping neutralizing anti-S Abs while driving the pandemic in a catastrophic direction, both in Israel and worldwide. How can the WHO stand by and watch as this additional experiment unfolds, soon to be followed by other countries?
(*) I assume the authors meant to say “asymptomatic infection”