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 ).