COVID-19 vaccines: where we stand and challenges ahead

Abstract

In the eleven months elapsed since the identification of the SARS-CoV-2 virus and its genome, an exceptional effort by the scientific community has led to the development of over 300 vaccine projects. Over 40 are now undergoing clinical evaluation, ten of these are in Phase III clinical trials, three of them have ended Phase III with positive results. A few of these new vaccines are being approved for emergency use. Existing data suggest that new vaccine candidates may be instrumental in protecting individuals and reducing the spread of pandemic. The conceptual and technological platforms exploited are diverse, and it is likely that different vaccines will show to be better suited to distinct groups of the human population. Moreover, it remains to be elucidated whether and to what extent the capacity of vaccines under evaluation and of unrelated vaccines such as BCG can increase immunological fitness by training innate immunity to SARS-CoV-2 and pathogen-agnostic protection. Due to the short development time and the novelty of the technologies adopted, these vaccines will be deployed with several unresolved issues that only the passage of time will permit to clarify. Technical problems connected with the production of billions of doses and ethical ones connected with the availably of these vaccines also in the poorest countries, are imminent challenges facing us. It is our tenet that in the long run more than one vaccine will be needed to ensure equitable global access, protection of diverse subjects and immunity against viral variants.

Fig. 1. Twelve candidate vaccines currently in Phase III trial.

COVID-19 vaccines based on the whole inactivated SARS-CoV-2.

Fig. 2. Spike as a target for vaccine development.

Within a few months after the identification of the new SARS-CoV-2, the freely available data made by numerous laboratories around the world provided a defined picture of the virus structure and of the steps of human cell infection. A SARS-CoV-2 is an oily spherical particle containing a single-stranded positive-sense RNA of about 30 kb wrapped and coiled by the Nucleocapsid protein. The virus outer shell consists of three other structural glycoproteins: Spike, Envelope, and Membrane, and a lipid coating. On the surface of SARS-CoV-2, three Spike glycoproteins aggregate protrudes outside the pericapsid and may interact at a high affinity with Angiotensin-Converting Enzyme 2 (ACE2), an exopeptidase normally present on the outer surface of a wide variety of human cells. B The Spike protein consists of two domains, S1 and S2. In the most external domain, a region known as Receptor-Binding Domain (RBD), allows the high-affinity binding of the SARS-CoV-2 to the N-terminal domain of the ACE2. The progressive elucidation of the critical role of this interaction provided the key insights that spurred several developers of innovative vaccine to target the Spike protein and its RBD [2, 66]. The recent reports on the protective efficacy of vaccines based on different platforms targeting the Spike protein [–9] suggest that the freely available basic science data allowed to make a winning bet [10].

Fig. 3. Twelve candidate vaccines currently in Phase III trial: COVID-19 Vaccines based on Spike protein.

These vaccines are probably the most immunogenic also thanks to the combination with new adjuvants [14]. The exploitation of transgenic plants as producers of Spike protein could allow the production of large quantities of the vaccine at an extremely low cost.

Fig. 4. Twelve candidate vaccines currently in Phase III trial: COVID-19 Vaccines based on Spike protein mRNA carried by lipidic microparticles.

These vaccines were the first to be developed and tested on volunteers. At the time of writing the Pfizer – BioNTech BNT162b2 has been cleared by UK regulatory authorities. This “historical” vaccine approval paves the way for mass immunization in Western countries.

Fig. 5. Twelve candidate vaccines currently in Phase III trial. COVID-19 Vaccines based on Spike protein DNA carried by adenoviruses.

The Chinese Can Sino Ad5-nCoV and the Russian Gamaley Res. Inst. Sputnik V vaccines have already obtained a limited authorization and have been administered to sections of the population. Despite the excellent preliminary results and well-documented immunogenicity, the Phase III trial on AstraZeneca/University of Oxford ChAdOx1 vaccine provided provocative but somewhat contradictory results that require further study [8].