The new SARS-CoV-2 virus is an RNA virus that belongs to the Coronaviridae family and causes COVID-19 disease. The newly sequenced virus appears to originate in China and rapidly spread throughout the world, becoming a pandemic that, until January 5th, 2021, has caused more than 1,866,000 deaths. Hence, laboratories worldwide are developing an effective vaccine against this disease, which will be essential to reduce morbidity and mortality. Currently, there more than 64 vaccine candidates, most of them aiming to induce neutralizing antibodies against the spike protein (S). These antibodies will prevent uptake through the human ACE-2 receptor, thereby limiting viral entrance. Different vaccine platforms are being used for vaccine development, each one presenting several advantages and disadvantages. Thus far, thirteen vaccine candidates are being tested in Phase 3 clinical trials; therefore, it is closer to receiving approval or authorization for large-scale immunizations.
Several laboratories and pharma companies worldwide are developing an effective vaccine against COVID-19. Several vaccine candidates have been developed using different platforms and it seems we are close to witnessing the first emergency use approval for a SARS-CoV-2 vaccine. In fact, on December 2nd, the Pfizer/BioNtech vaccine become the first vaccine to receive approval for emergency use in the UK. Since then, the Moderna and Oxford/AstraZeneca vaccines have also received EUAs from several drug regulating agencies and vaccinations have began in several countries. Earlier, in the third trimester of 2020 other leading candidates had also been granted approvals for limited use in China, Russia, and U.A.E.
The vast majority of SARS-CoV-2 vaccines under development require a prime-boost regimen. Massive vaccination campaigns would therefore require billions of doses to satisfy global demand. For the first time in vaccine development history pharma companies are scaling up at risk production, without knowing if their candidate will receive authorization, but in theory will still require years to produce these numbers. This means that since the first candidates were authorized for wide use governments had to chart prioritization strategies. High vulnerability groups such as health workers and indispensable professionals are the first to receive a vaccine, followed by age groups older than 65 years. On the other hand, more strategic alliances are constantly forming between pharmaceuticals and institutions to increase SARS-CoV-2 vaccine production sites worldwide and maximize the production of vaccines on large scale to meet global demand.
Cold chain issues for different platforms can also be a decisive factor for their widespread use. Nucleic acid and -sometimes- viral vector platforms that require long-term storage at −70 °C from fabrication to administration can raise severe problems for the distribution of the respective vaccines and limit their use in rural areas.
Another caveat is that we have not yet defined which the correlates of protection against COVID-19 or SARS-CoV-2 infection are. It is important to pinpoint the exact antibody titers that confer protection or the details of T cell responses that result in asymptomatic or mild disease. Knowing the correlates of protection will provide us with specific measurable aspects of immune response needed to thwart severe disease or even prevent infection. Further research is also needed to explore the durability of the immunity induced by each vaccine. We already know that infection by human coronaviruses produces humoral immunological memory that ranges from months to a couple of years, but long-term data on SARS-CoV-2 immunity are still lacking.
An additional consideration is the absence of children and pregnant women -and other vulnerable groups- from clinical trials conducted so far. It is quite probable that these groups will have to wait for additional small-scale clinical trials after the first generation of vaccines has been approved for other adult groups.
A possible problem might be that the first generation of SARS-CoV-2 vaccines will probably not confer sterilizing immunity against SARS-CoV-2 as current Phase 3 trials are evaluating candidate efficacy for disease prevention rather than infection prevention.
All the leading vaccine candidates are administered via intramuscular injection. However, results emerging from several recent studies highlighting the importance of mucosal immune responses against SARS-CoV-2 infection. These suggest that intranasal administration as a more attractive strategy to marshal early protective immune responses in the upper respiratory tract mucosa before SARS-CoV-2 gains a foothold in the lower respiratory tract. Several vaccine candidates are exploring this potential. Accordingly, Maryland-based company Altimmune is recruiting volunteers for a Phase 2 clinical trial with their intranasally administered vaccine candidate called AdCOVID (Clinical Trial Identifier: NCT04442230), whereas China will begin Phase 1 clinical trials on an intranasally administered vaccine candidate for COVID-19 as announced on early September. AdCOVID is an adenovirus type 5 (Ad5)-vectored vaccine encoding the RBD of the SARS-CoV-2 S protein. In a recent pre-print, AdCOVID intranasal administration was found to confer protective immunity in murine models eliciting robust cellular and humoral immune responses against RBD and resulting in the production of mucosal IgA. Additionally, San Francisco-based Vaxart has also designed an Ad5-based oral SARS-CoV-2 candidate given in a form of a tablet. When they tested a candidate that encodes full-length S protein of SARS-CoV-2 in mice they detected induction of higher titer SARS-CoV-2 specific antibodies both in the bloodstream and in the lungs, along with the production of antigen-specific CD4+ and CD8+ T cells. On September 21st, Vaxart’s candidate named VXA-CoV2-1 entered Phase 1 studies enrolling 48 healthy adult volunteers aged 18–54 years old (Registration Number: NCT04563702). Merck and IAVI are also developing a recombinant VSV viral-vectored SARS-CoV-2 vaccine in the form of a tablet. This approach is similar to the ERVEBO vaccine against Ebola designed by Merck. On October 30th, V590—as is the current candidate’s name—entered Phase 1 trials and will be administered to 252 volunteers aged 18–54 years old (Registration Number: NCT04569786). Finally, Canada-based company Symvivo announced on November 2nd, that they began a Phase 1 clinical trial using a DNA vaccine platform, whereby the DNA is inserted and replicated in probiotic bifidobacteria which then are administered orally in a liquid form, delivering the DNA codifying for the S protein of SARS-CoV-2 in intestinal epithelial cells, which then express and present the viral protein. The bacTRL-Spike vaccine candidate will be delivered in 12 participants in different concentrations (Registration Number: NCT04334980) that will be studied for safety and immunogenicity parameters. Additional clinical trials are conducted with existing vaccines that do not specifically target SARS-CoV-2, but instead aim to activate trained immunity responses that could partially protect against SARS-CoV-2 infection or disease severity.
Since the first SARS-CoV-2 vaccines received emergency use approvals, a race against the clock has begun to provide an enormous number of doses and immunize vulnerable populations globally in a prioritized fashion. However, this titanic effort might be curtailed by vaccine hesitancy. Indeed, surveys of vaccination intention have shown that in the US only 40-50% of the general population plan to be vaccinated once a SARS-CoV-2 vaccine will be made available and this problem needs to be addressed promptly.
In spite of that, the only strategy to achieve herd immunity for COVID-19 and be able to return to pre-pandemic normality is a safe and efficient vaccine that would not only be able to prevent severe COVID-19 symptomatology but minimize viral load or even prevent infection and generate immune memory responses for a minimum of 1 year.
Conclusions The world is in the midst of a COVID-19 pandemic and the entire vaccinology scientific community is racing to find a vaccine against SARS-CoV-2 that is safe and effective. There are currently more than 230 vaccine candidates under development, with a number of these already receiving EUAs within less than a year since the first report of a SARS-CoV-2 infection.
Ethics committees are revising their authorization protocols, and pharmaceutical companies have formed strategic alliances with vaccine developing institution in order to ramp up production of vaccine candidates at risk. More than 150 countries have entered the COVAX initiative and other alliances that will aim to ensure an equitable distribution of an approved vaccine.
Several governments have made up-front payments to secure a number of doses of the vaccines under development that will help to return to a pre-COVID-19 normality.
However, several aspects of anti-SARS-CoV-2 immunity are still unknown and more specific conclusions about the correlates of protection against SARS-CoV-2 infection are expected to be drawn together with the initial results of Phase 3 trials. The vast majority of the vaccine candidates aim to elicit neutralizing antibodies against the S protein of the virus, thereby inhibiting the viral particle recognition and uptake mediated by human ACE2 receptor binding. Indeed, the majority of published clinical study results compare the neutralizing antibodies elicited with by immunization with the vaccine candidates against the neutralizing antibody levels averagely produced in convalescent COVID-19 individuals. In this regard, most preliminary results are quite promising as different candidates were found to induce higher neutralizing antibody titers than natural infection. An increasing body of evidence suggests that T cell mediated response is an arm of coronavirus immunity. Accordingly, vaccine platforms that also activate this arm of adaptive immunity, such as viral vectored or nucleic acid vaccines, are gaining favor among experts. Developing multiple vaccine candidates that employ different vaccine delivery systems will probably prove to be crucial in the fight to end the COVID-19 pandemic. On one hand, several vaccination options, if approved, will enable us to produce the necessary doses for massive vaccination in a shorter timeframe. On the other hand, it is quite possible that different vaccine platforms will exhibit different grades of protection against specific population groups with altered immune responses such as children, pregnant women, immunocompromised populations due to comorbidities, and immunosenescent age groups ≥65 years.
Meanwhile, several clinical trials are exploring whether already approved vaccines can confer a certain grade of protection against COVID-19. The Bacillus Calmette–Guérin (BCG) vaccine and the MMR (measles, mumps, and rubella) vaccine are known to elicit strong immune responses with the activation of both specific and non-specific T cell populations. This bystander activation of heterogeneous T cell populations along with trained innate immunity mechanisms have been shown before to protect against viruses of the respiratory tract.
Finally, several critical aspects of SARS-CoV-2 immunity will be elucidated as a result of massive vaccination campaigns. The durability of the immunity induced by the different vaccine strategies as well as the fine details of the immune responses elicited will emerge as bigger populations get vaccinated, including individuals with suboptimal immunity.
Reference & Source information: https://www.nature.com/
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