In January 2021, we wrote a letter to the editor of the Journal of Global Antimicrobial
Resistance about the possible role of vaccine or monoclonal therapy in the fight against
SARS-CoV-2 [1]. The virus had already been infecting the world for 12 months and the
first variants were emerging, such as the UK variant, B.1.1.7, characterized by a
large number of mutations, and the South Africa variant, B.1.351, which emerged independently
of B.1.1.7.
All our hopes were placed on vaccines, such as BioNTech/Pfizer, Oxford/AstraZeneca,
Moderna, Sinovac, CanSino, Sinopharm, Novavax, and others [1]. However, the first
debates had already begun on the usefulness of these vaccinations as new variants
were emerging, raising the possibility of infection for recovered/vaccinated subjects.
Some reports outlined cases of SARS-CoV-2 reinfection from different countries, including
the USA, Ecuador, Hong Kong, and Belgium [2]. The researchers argued on the necessity
of verifying whether all these cases were truly reinfection because the possibility
of reinfection could drastically reduce the effectiveness of the vaccination campaign
and affect government and public-health policy decisions. Cases of COVID-19 were subsequently
described in subjects treated with two, or even three doses of vaccine [3], causing
doubts in part of the population about the usefulness of vaccination for SARS-CoV-2
and the formation of No-Vax groups.
In the meantime, however, the virus has shown great mutational capacity, so now we
are talking about variants Alpha, Beta, Gamma, Delta, Epsilon, Iota, Kappa, Lambda,
Mu [4]. This COVID-19 alphabet shows that, in two years of travelling around the planet,
the virus is accumulating one new variant after another. The variants are not becoming
increasingly dangerous – indeed, most of the coronavirus transformations are harmless.
The Alpha variant had already distinguished itself for the greater speed of contagion
compared to the original SARS-CoV-2 virus; the Beta affected younger subjects, between
10 and 30 years; Gamma and Epsilon made the already recovered sick again. Lambda has
been found to be particularly infectious [5].
In the evolutionary dance for survival, mutations emerge periodically and result in
a turbo-charged virus. The Delta, born in India, has this enhanced “engine” that allows
it to be transmitted in a few seconds [6]. Will it be the last ace up the sleeve of
the SARS-CoV-2, or is it a taste of what awaits us in the future? Are these variants
biological disguises that will deceive vaccines and bring us back to the days of intensive
care units crowded with gasping patients?
Of all the variants, Mu, first identified in Colombia in January 2021 and now identified
in at least 39 countries, appears to be the most worrying, as it has a similar transmission
speed to the Delta and is enhanced by other mutations, which could, in theory, allow
it greater resistance to being neutralized by antibodies [4].
At the moment, the strategy of the virus seems not to be trying to escape the antibodies
but running faster, transmitting itself with particular ability in aerosols and with
a shorter incubation period than previous variant of the virus.
However, with a growing vaccinated population, the virus could modify its strategy
by selecting mutations that are able to escape vaccinal immunity. The main drug companies
are modifying their vaccines to make them more efficacious against the Delta variant.
This process could take months, however, and there is a risk that these new vaccines
could be overcome by even newer variants.
SPECIAL PATIENTS AND VACCINES
An unprecedented problem that has emerged in the fight against the SARS-CoV-2 pandemic
is the use of nucleic acid-based vaccines in fragile patients, such as those undergoing
solid organ transplantation (SOTRecipients). These individuals are at greatest risk
of various infectious diseases, and vaccinations are among the most efficient available
interventions for inducing effective immunizations. There are currently no consolidated
scientific data to support the safety and efficacy of nucleic acid-based vaccines
(DNA, RNA) in organ transplant recipients. Solid organ transplant patients are at
high risk of poor outcomes with COVID-19. In fact, a recent European study found a
20% mortality in liver transplant (LT) recipients with SARS-CoV-2 infection, markedly
higher than in the general population, highlighting the potential benefits of vaccination
in these recipients [7]. In addition, the safety and immunogenicity of SARS-CoV-2
mRNA/DNA vaccines have never been clinically tested previously in SOTR. Public health
guidelines prioritized SOTR for vaccination as high-risk populations, but more data
are required about the real potentiality of vaccines against SARS-CoV-2 in these patients,
such as the level of immune response, the efficacy of the immune response, and the
best choice of vaccine.
NEW WEAPONS IN THE FIGHT AGAINST SARS-COV-2
In light of all these considerations, chasing the virus might not be the winning strategy
and it should not give us too much confidence. An advisable strategy would be to start
producing other types of vaccines in the form of a spray with the objective to induce
local immunity in the respiratory mucosa, as already exists for the flu, blocking
the entrance door of the virus. Ohtsuka et al. [8] developed an intranasal vaccine
against SARS-CoV-2 using the replication-incompetent human parainfluenza virus type
2 (hPIV2) vector BC-PIV. This vaccine can deliver an ectopic gene as stable RNA and
an ectopic protein on the envelope that is able to induce high levels of neutralizing
IgG and mucosal IgA antibodies in mice, against the spike protein. University of Oxford
researchers are now conducting an open-label clinical trial of the intranasal vaccine
in healthy human volunteers [9].
Photo: Intranasal vaccine against SARS-CoV-2. Source: from BioRender (license granted
to author).
De Vries et al. [10] designed lipopeptide fusion inhibitors that block the critical
first step of infection – the membrane fusion between the viral and host cell membranes
– which is mediated by the viral spike protein. Daily intranasal administration to
ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour
cohousing with infected animals, under stringent conditions that resulted in infection
of 100% of untreated animals [10]. These lipopeptides are highly stable and thus may
readily translate into safe and effective intranasal prophylaxis to reduce transmission
of SARS-CoV-2 [10].
Another possible strategy is to use innovative treatment alternatives such as monoclonal
antibodies that could offer short-term protection to those who are not yet vaccinated
or who lack a proper response to vaccination, such as immunocompromised patients.
Additionally, mAbs could prove helpful during times when circulating variant viruses
are not adequately covered by vaccines protection [11]. Moreover, because a certain
time is required after vaccination to develop a proper immune response, the benefits
of passive immunization are evident in numerous settings where outbreaks are frequent.
Some studies are evaluating the potential role of mAbs for prevention of infection
or symptomatic disease, such as the phase 3 BLAZE-2 trial (NCT04497907) designed to
evaluate the efficacy and safety of bamlanivimab (4200 mg, iv), the Part A of the
Regeneron trial (NCT04452318) designed to assess the efficacy and safety of the subcutaneous
administration of casirivimab plus imdevimab (600/600 mg) in preventing SARS-CoV-2
infection, the PROVENT trial (NCT04625725) and the STORM CHASER trial (NCT04625972),
designed to study the combination of two long-acting antibodies (cilgavimab + tixagevimab),
developed from the B-cells of a convalescent donor after the infection [12].
In order to convince the most fearful subjects, some researchers are examining the
possibility of mAbs administration via nasal sprays or aerosolized formulations, and
early clinical studies confirmed that this approach is safe and can be used to prevent
and treat SARS-CoV-2 infection.
Other alternative possibilities in the fight against SARS-CoV-2 could be nanotechnology
applications such as viral inactivators (including cellular nanosponges) for reducing
viral adhesion, or the treatment of personal protective equipment (PPE) with charged
metallic (such as Cu, Ag, Fe and Zn among others) nanoparticles, which seems to result
in the release of antiviral agents (ie, reactive oxygen species) which are able to
inhibit viral entry into host cells by means of interactions with cell receptors [13].
Nanotechnology offers a way to improve the safety offered by personal protective equipment
by modifying their surface, ensuring not only the capture and inactivation of viruses,
but also the reusability and washability, without compromising the efficiency and
safety [14].
CONCLUSIONS
In conclusion, because we are lacking standardized means to predict guaranteed immunity
in 100% of recipients, it is necessary to continue to develop alternative strategies
to vaccines in the fight against SARS-CoV-2.