The possible impact of emerging SARS-CoV-2 variants on vaccine efficacy, SARS-CoV-2 infection age-distribution and severity, and the need to still maintain physical preventive actions
Since no hospital admissions or severe cases were reported in the ChAdOx1 nCoV-19 arm (2,3 ), the data clearly show that ChAdOx1 nCov-19 is still effective against severe and persistent disease during emergence of UK variant. Indeed, a single dose of ChAdOx1 nCoV-19 (or BNT162b2) vaccine significantly reduced rates of both infections and hospitalisations/deaths during a period in which B.1.1.7 was dominant in UK (between 1 December 2020 and 3 April 2021) (19 ). It is clear that the number of both infected individuals and days of infectivity (related to severity) per person substantially influences the probability of both virus transmission and mutation (i.e. generation of variants). Therefore, at the moment, ancestral spike-based vaccines are able to reduce the severity of symptoms and the time of infectivity and transmissibility of UK variant; however, care should be taken because asymptomatic infection in vaccinated individuals may spread the variant over the non-vaccinated population, albeit at lower efficiency (19 ). Indeed, if the vaccinated individuals do not maintain everyday preventive actions (such as the physical distancing and the use of face masks), they might turn into potential spreaders not only to uninfected and unvaccinated individuals but potentially also to some individuals that were asymptomatic during the first wave but susceptible to new and highly infectious SARS-CoV-2 variants (e.g., B1.1.7).
Under the selective pressure of the immune system in convalescent or vaccinated people, adaptation processes of mutable RNA viruses (such as SARS-CoV-2 and influenza) constantly generates a heterogeneous pool of SARS-CoV-2 variants, which are continuously tested and selected “in vivo” in order to escape immune responses, antibody treatments and herd immunity. For example, SARS-CoV-2 spike variants with increased binding affinity to human ACE2 (such as N439K variants, 17 ) can probabilistically lead to a higher number of infected both cells in a patient and individuals in a population. Therefore, they can produce a worse and persistent infection in a broader range of humans, also providing an increased probability of transmission, which is a strong competitive advantage. Moreover, the accidental ability of reinfection or of infection of vaccinated individuals provides a competitive advantage to some SARS-CoV-2 variants, particularly in highly vaccinated countries, in which most people are fully resistant to the ancestral virus. If the vaccinated people become susceptible to a variant infection, this variant will have plenty of people to infect again, potentially leading to a “rebound” effect in highly vaccinated countries (as it may occur for example in Chile, see 20 ), which, in this globalisation world, will potentially spread the new variant to less vaccinated countries (potentially turning “vaccinated” countries as well as individuals into potential spreaders that might lead to a sort of an involuntary biological world war). Fortunately, the nature of the new vaccine technology will rapidly allow for new vaccine variants with specific mutations; however, it is not clear how many vaccinations with different vaccine variants will be necessary before ending the pandemic (and recovering the global economy) and what will be the short- and long-term consequences in efficacy and antibody dependent enhancement (ADE) (21 ) of repeated vaccination. In this regard, yearly viral challenge of influenza virus is a good model to try to predict the effect of repeated exposures to mutant viruses and seasonal vaccine variants. Indeed, influenza vaccines successfully control the severe forms of infection; however, it has been observed that some previous infections and/or vaccinations with influenza strains can be sometimes counter-protective (22 ). Interactions between the immune system and mutant pathogens and/or vaccine variants are dynamic processes, which evolve at each exposure on the basis of previous host-pathogen interactions “memorized” by the immune system of each individual and, by extension, of each population/community (22 ). The imprinting event of first influenza infection or of first vaccination generates a pool of long-lasting immunological memory cells which remains throughout life and determinates the response to subsequent infections/vaccinations. It has been hypothesized that an elevated antigenic diversity between previous and subsequent vaccination permits the generation of new immune memory cells that better protect from viral infection. Conversely, repetition of antigenically-related vaccines and previously existing low avidity antibodies derived from memory cells can lead to a deleterious outcome of a subsequent infection by causing ADE (22 ). Therefore, cumulative effects of subsequent influenza virus infections and/or vaccinations can “unpredictably” shape future immune responses that could be either beneficial or deleterious (22 ). Regarding the eventuality of repeated SARS-CoV-2 spike vaccinations, there is a further aspect of unpredictability due to the fact that influenza vaccines include inactivated influenza vaccine, live attenuated influenza vaccine, or recombinant protein influenza vaccine, instead the SARS-CoV-2 vaccines that have recently received emergency use authorisation in Europe include lipid nanoparticle-encapsulated mRNA based vaccines or adenovirus-vectored DNA based vaccines. When compared to traditional vaccines that use dead or weakened forms of the viruses, these new vaccines have an important difference in the envelope that contains the genetic material. The envelope is the vector that determines not only anti-envelope/vector immune responses but also the cells in which the genetic content is inserted and expressed, the vaccine tropism. Differently from traditional vaccine platforms, the novel vaccine strategies induce anti-envelope/vector immune responses which are not functional to generate anti-viral memory cells and insert the spike nucleotide sequence into cells independently on ACE2 expression, possibly driving a non-specific immune response against cells that will never be infected by SARS-CoV-2. Therefore, in order to reduce current pressure on healthcare systems, vaccination should be focused on protecting from severe disease the most vulnerable (minority) part of the population for which the risk/benefit balance of vaccination is more favourable. At the same time, this vaccine strategy (successfully applied for highly mutable influenza RNA virus, for which we have never tried and needed to reach a herd immunity) will likely limit vaccine-driven immune selection pressure that, under current conditions of very high levels of virus replication and diffusion, might facilitate viral immune escape mechanisms.
Of particular concern are variants that are able to generate a persistent immune system’s fight against viral infection in people with strong immune responses (such as young healthy people). Indeed, the accidental ability of virus variants not only to produce persistent infections in a broader number of individuals including young and healthy people (who are relatively resistant to ancestral infection) but also to “survive” in different environmental conditions (e.g. different seasons) provides a higher probability of transmission and a competitive advantage. Indeed, SARS-CoV-2 variants, which persist during summertime and are more resistant to summer temperatures, humidity and UV rays, are already present in South Africa, Brazil, Chile and India, countries in which the variants emerged during their summer. Moreover, future variants able to produce persistent (asymptomatic and/or symptomatic) infection in a broader spectrum of humans are also expected to be selected. In this regard, during the second wave of SARS-CoV-2 (September 2020 to January 7, 2021), there were more people (and in a shorter time period) in England’s hospitals with COVID-19 (weekly incidence per 100000 inhabitants was 19.3 cases, calculated using the 2019 population estimates for the England available from the UK National Statistics) than in the first wave (March to September 2020, weekly incidence per 100000 inhabitants was 6.4 cases), indicating the higher infectivity of UK SARS-CoV-2 variant (see 23 ). In particular, there was a relative increase in hospitalization rates in younger age groups (1.72-fold increase for the <17-year age group) compared to the older age groups (1.35-fold increase for the >65-year age group), while relative increase was intermediate (1,46-fold) for the 18-64-year group (see 23 ). During the first wave of SARS-CoV-2, the prevalence of hospitalisation for COVID-19 was 1 young (in the <17-year age group of 12023568 individuals based on the 2019 population estimates for the England) every 64 elderly (in the >65-year age group of 10353716 individuals based on the 2019 population estimates for the England), i.e. relative risk ratio 0.016 [99% CI 0.015–0.017], while it significantly increased to 1 every 50 individuals, i.e. relative risk ratio 0.020 [99% CI 0.019–0.021] in the second wave, thus leading to a substantial decrease of the median age of hospitalized patients compared to the first wave. In line with this observation, a recent report observed a shift in the age composition, with significantly more UK variant cases among individuals aged 0-19 and significantly fewer UK variant cases among individuals aged 60-79, as compared to non-UK variant cases (24 ). However, at this time it is not possible to predict whether (spontaneous and vaccine-driven) immune pressure could quickly induce a mild endemic disease or whether this could occur over the course of years, passing through a more aggressive and severe disease, and how mass vaccination may influence its development (this information will rapidly be available in highly vaccinated countries). In this regard, a recent report estimated that infection with a new variant of B.1.1.7 lineage spread in UK during December 2020 has the potential to cause substantial additional mortality compared with previously circulating variants (54906 matched pairs of participants between 1 October 2020 and 29 January 2021), increasing the probability of risk of mortality from 2.5 to 4.1 per 1000 detected cases (25 ). Results that are in agreement with those of another recent report (26 ) and suggest that at the moment the progression of the disease is becoming worse.
For all the above considerations, although vaccine strategies may temporary reduce both disease severity and spread, are unlikely to prevent the appearance of new variants and to be effective in quickly solving the pandemic crisis. It is instead likely that global herd immunity will be slowly achievable by vaccination and neutralizing antibody strategies. Therefore, there is the need to keep searching for new pharmacological therapies and more scientific efforts should be directed towards pharmacological approaches that, working downstream the infection pathways, are independent on virus variant. In this regard, clinical trials employing new safe pharmacological treatments for COVID-19 with a potentially effective mechanism of action that are not tested in clinical trials yet, such as chelating agents, bismuth based or other antiviral drugs, are urgently needed (see 27-30 ).