Unravelling the complexity of a pandemic shaped by mass vaccination. What does it tell us?

Advanced mass vaccination campaigns conducted in the vulnerable part of the population lead to diminished viral infection rates. This not only results into declining morbidity and mortality rates in this population but also reduces the likelihood for previously asymptomatically infected persons to become re-infected shortly after their primary infection. This is to say that mass vaccination of the vulnerable will make it increasingly unlikely that previously asymptomatically infected persons become re-infected while experiencing substantial suppression of their natural Abs (as suboptimal, S-specific Ab titers rapidly decline in the majority of asymptomatically infected people). Hence, the likelihood that this part of the population contracts Covid-19 disease as a result of re-exposure will, therefore, shrink as well.

The more mass vaccination of the vulnerable group advances, the higher the chance for previously asymptomatically infected subjects to become re-exposed to Sars-CoV-2 at a point in time where their suboptimal S-specific Ab titers are no longer high enough to sufficiently block their natural Abs to cause Covid-19 disease but are still high enough to exert immune pressure on viral infectiousness. The more the mass vaccination program extends to lower age groups, the less will be the effect thereof on viral infectious pressure and the more the number of subjects experiencing suboptimal S-directed immune pressure will grow. Consequently, opportunities for variants that have been selected to overcome this immune pressure will improve when vaccine coverage rates incline. In countries that are expanding their mass vaccination program on a background of a relatively high infectious pressure (e.g., Chile, Uruguay, France, Germany, USA, Hungary, Belgium; current vaccination rates [single dose] between 30 and 37%), vaccine-resistant variants are expected to dominate previously circulating, more infectious variants at vaccine coverage rates that are significantly lower than in countries with much lower infection rates (e.g., Israel, UK; current vaccination rate [single dose]: 63 and 53%, respectively). Depending on the infection rate and rate of vaccination, progression to vaccine-resistant variants may transition through a stage wherein even more infectious variants are circulating for a more or less limited period of time.

The way ongoing mass vaccination campaigns diminish viral infectious pressure is very different from the one thought to control viral infection during a natural Covid-19 pandemic. Based on observations and data from the 1918 Influenza pandemic, the infectious pressure during a natural Covid-19 pandemic would gradually and durably decrease as vulnerable subjects who contracted Covid-19 disease (including those who were asymptomatically infected during the 1st wave and, as a result, had become susceptible later on) recover. Their recovery after the 1st and 2nd wave of disease results in a gradual increase in acquired herd immunity. As it takes time for the virus to spread, different susceptible parts of the population would be infected or re-infected at different time points. This would ensure that at any given point in the transmission chain the morbidity level and hence, the infectious pressure, remain high enough to cause Covid-19 disease in yet another set of susceptible, previously asymptomatically infected subjects while enabling the population to gradually increase its herd immunity. Only when grown beyond a threshold that no longer provides for sufficient infectious pressure would the level of herd immunity prevent further waves of disease and death. However, as healthy, asymptomatically infected subjects can spread the virus as well (although to a lesser extent) and tend to develop suboptimal anti-S Abs following exposure, it is reasonable to assume that the remainder of this group could serve as a reservoir for Sars-CoV-2 transmission and thereby enable selection of more infectious immune escape variants. However, as the majority of the population will have acquired memory B cells capable of recalling high avidity anti-S Abs upon re-exposure to Sars-CoV-2 and as Abs recalled from a previous infection with live virus may also efficiently neutralize more infectious variants, it will become more difficult for Sars-CoV-2 to augment its infectious pressure beyond a threshold high enough to provoke disease in this reservoir. It is fair to postulate that waves of morbidity and mortality could be prevented under the premise that people adhere to some elementary public health and social measures.

The above-described course of viral transmission is very different from the one observed when mass vaccination campaigns are conducted during the course of a pandemic of a mutable virus which naturally causes acute, self-limiting infection. Let’s consider ongoing Covid-19 mass vaccination campaigns. So far, these campaigns have primarily been targeting vulnerable individuals (i.e., elderly, people with underlying diseases or at high risk of infectious exposure or experiencing immune suppression). Vaccination of these subjects provides them with protective, S-Ab-based adaptive immunity and hence, reduces infectious viral pressure. Diminished infectious pressure leads to a diminished morbidity rate in previously asymptomatically infected subjects. This gradually increases the likelihood for these subjects to become exposed to the virus while merely exerting suboptimal S-directed immune pressure instead of succumbing to Covid-19 illness. Mass vaccination, therefore, reduces the capacity of previously asymptomatically infected individuals to contribute to herd immunity but instead augments their capacity to serve as a breeding ground for more infectious variants. The faster vaccination rates rise (i.e., the faster previously asymptomatically infected subjects are turned into vaccinees), the faster this population will start to exert immune pressure on vaccinal Abs upon re-infection with Sars-CoV-2. However, in case mass vaccination progresses on a background of low infectious pressure, it may take some more time for the virus to raise the infectious pressure up to a level that supports adaptation of Sars-CoV-2 to suboptimal S-directed immune pressure. This is because asymptomatically infected vaccinees and non-vaccinated, previously asymptomatically infected subjects typically shed less virus than people who contract Covid-19 disease.

It is important to note that immune pressure and, therefore, adaptation of selected immune escape variants will be increased over-proportionally when enrolment of younger age groups (e.g., < 65 years) becomes significant. It is reasonable to postulate that administration of the 2nd dose of vaccine on a background of more infectious variants will only expedite selection and adaptation of variants capable of resisting a full-fledged vaccinal Ab response. It goes without saying that infection with variants that are fully resistant to the vaccines will result in a dramatic increase in morbidity and mortality rates, not at least in vaccinees .

Even though mass vaccination campaigns have not yet led to selection and enhanced circulation of vaccine-resistant variants in most countries, they are increasingly optimizing the conditions for more infectious variants to further evolve their resistance to S-specific Abs. The higher the vaccine coverage rate in general and that of younger age groups in particular, the better these variants will thrive and resist S-specific Abs of growing affinity (i.e., elicited after 2nd as compared to 1st dose of vaccine) and the faster they will dominate previously circulating variants.

Pending enrolment of younger age groups the situation is now expected to dramatically expedite the propagation of the Indian mutant to then rapidly evolve towards circulation of dominant variants that are completely resistant to the vaccines, even upon administration of the second dose.


Whether ‘home-made’ or ‘foreign’, vaccine-resistant variants are highly likely to cause more (severe) disease in vaccinated as compared to non-vaccinated subjects. This is because the latter may still dispose upon a fully functional arsenal of CoV-nonspecific Abs provided they are seronegative for CoV-derived S protein. As a result, vaccinees will soon constitute the predominant source of Sars-CoV-2 infection and cause a dramatic surge in viral infectious pressure. As pre-symptomatic vaccinees will increasingly serve as a reservoir for Sars-CoV-2 infection, non-vaccinated persons should refrain from mixing with vaccinees.

As patients with severe Covid-19 disease need hospitalization, circulation of vaccine-resistant variants is not only going to overwhelm the health care system but also pose a tremendous risk to all health care workers as the vast majority of them have already been vaccinated. Consequently, health care workers as well will be much more susceptible to contracting Covid-19 disease caused by vaccine-resistant variants.

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