COVID-19 vaccine design and vaccination strategy for emerging variants

Since the beginning of the pandemic, new ‘severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)’ variants that have the ability to influence the airborne transmission, virulence, and immune evasion of affected individuals emerged [1]. Variants of SARS-CoV-2 may be categorized based on their statistical distribution among phylogenetic groupings; Figure 1 summarizes the prominent mutations of novel coronavirus. As per ‘Global Initiative for Sharing all Influenza Data (GISAID),’ a total of eight clades of SARS-CoV-2 with genetic markers have been identified and characterized. In contrast, lineages have been categorized based on genetic and epidemiological variables associated with epidemics in distinct geographic locations [2]. Genes related to viral nucleocapsid protein with mutants of ORF1a and ORF1b are thought to be involved in asymptomatic situations. Similarly, the presence of D614G, Q57H (ORF3a), and S194L mutations are related with hospitalization cases [3,4]. A single-nucleotide mutation (nt14408) in RdRp is linked to severe illness [3,5]. Multiple variables including age and underlying disorders are involved in the progression of COVID-19 and have a bearing on its severity. Nonetheless, the link between mutants and clinical outcomes has not yet been exhaustively investigated; further studies are required to uncover potential correlations between SARS-CoV-2 variants and sickness behavior. Meanwhile, updated vaccines are being developed, and it is essential that monitoring of mutations of the virus continues to be conducted in tandem with trials to clarify the phenotypic effects of mutations [6].

Figure 1. Prominent SARS-CoV-2 spike protein mutations in different variants. Most frequent mutations (red color) in the SARS-CoV2 spike protein determined by clustering and alignment methods. The two subunits of the S protein are S1, which contains the RBD (magenta) and the N-terminal domain (yellow), and S2 (marine). The ACE2 binding site on the RBD is shown in green, and the fusion peptide in orange. Most high-frequency mutations were detected in the RBD and the NTD. (Adapted from Negi et al [7] under creative commons attribution 4.0 international license).

During the epidemic situation, the rapid development and commercial availability of COVID-19 vaccinations has been a bright spot. This has been made feasible in large part by the availability of major financial resources from governments, people, institutions/international organizations, and philanthropists, as well as the results of focused worldwide partnered medical and clinical endeavors. Developing COVID-19 vaccinations in less than a year was one of the most important advances in the history of medical science. However, with the advent of new COVID-19 mutants, future research must concentrate on vaccines that have the capacity to prevent transmission or infection of new variants. Nonetheless, a number of significant challenges remain, such as the unequal availability and distribution of such vaccinations around the world, their price, and the rise in vaccine reluctance [8].

Although COVID-19 vaccinations are an essential tool, none of them are 100% effective at preventing COVID-19 infection. A small fraction of the completely vaccinated population will still get COVID-19 illness to variable degrees [9]. As of May 2022, there were 38 vaccines approved under the emergency usage path (EUA) in at least one country. Almost 60% of the world population have received a primary dose of any EUA vaccine. A vaccination breakthrough case is defined as a person with SARS-CoV-2 RNA or antigen found on a respiratory specimen taken at least 14 days following completion of the first series of a US FDA-approved COVID-19 vaccine [10]. In almost all the vaccination studies, pregnant and nursing women, the immunocompromised, and varied racial and ethnic groups have been under-represented. Even before the pandemic, clinicians had to deal with the problem of vaccine refusal. There is an increasing lack of confidence in the COVID-19 vaccination. The equitable distribution, storage needs, and cost of vaccines will have a huge influence on regions around the globe.

Computational immunology is without a doubt the trump card underlying the rapid creation of SARS-CoV-2 vaccines. For further quick and accurate vaccine creation, bioinformatics, vaccinogenomics, immunoinformatics, structural biology, and molecular simulations may be applied in silico [11]. These data processing findings are a crucial asset for advancing the burgeoning area of immuno-informatics that focuses on the detection of potential antigenic epitopes in virion that may be exploited in the construction of a vaccine composition inducing an immunity. For the validation of prospective vaccination targets, bioinformatics platforms, computational tools, and databases are also necessary [12]. Molecular dynamics modeling, molecular docking, and artificial intelligence technology of bioinformatics methodologies based on drug databases may speed the discovery of antiviral medicines for SARS-CoV-2. Meanwhile, computational methods like as reverse vaccinology, immunoinformatics, and structural vaccinology are useful for identifying effective vaccines against COVID-19 infection [13]. Using these techniques, new improved vaccines can be designed including vaccines to emerging variants where epitopes and mutant areas are included. However, as these techniques use synthetic pseudo-viruses, they lack serological correlations, which is a significant disadvantage [14]. Despite this, rapid structural identification of mutant regions can be viewed and new vaccines designed which will require in vivo immunogenicity studies and toxicology prior to clinical trials. As a stand-alone, computational studies cannot translate new designed vaccines to human trials as they cannot predict humoral and cell mediated immunity. Importantly, there have been inconsistencies between the findings of the pseudo-virus neutralization tests and the real viral neutralization assays, which can only be addressed with clinical data against all variant viruses [15].

Intriguingly, and despite concerns regarding ‘vaccine-associated enhanced disease (VAERD),’ the second quickly developed vaccine platform was a much older technology, viral inactivation. The availability of numerous vaccine platforms further increased the number of vaccines under development and, therefore, the production capacity [16]. VAED contains antibody-dependent enhancement (ADE), antibody-enhanced disease (AED), and Th2-mediated pathology [17]. Acute respiratory distress syndrome may be caused by a number of stressors, including SARS-CoV-2 infection, induction of inflammation, alveolar cell destruction, surfactant malfunction, and other vascular and hematologic abnormalities. All instances of vaccination failure should be investigated for the likelihood of VAED/VAERD, however not all instances of VAED/VAERD will be a result of vaccine failure [18]. Where possible, a comprehensive investigation of different etiologies should be conducted, to assess prospective instances.

In addition, rare adverse effects have been recorded post vaccination, including thrombosis with thrombocytopenia syndrome (TTS), allergy, myocarditis, and Guillain–Barré syndrome [19]. Despite the fact that the Ad26.CoV.S vaccine mitigates all of these uncommon adverse effects, anaphylaxis and myocarditis mostly occur following vaccination with mRNA-based vaccines, and TTS is connected with adenoviral vector-based vaccinations [20]. To completely comprehend the relationship between COVID-19 vaccinations and uncommon adverse effects, further studies are necessary, as are long-term studies of delayed vaccination responses. In the end, laboratory-based findings are only partially accurate since they do not reflect a complicated human body process. In order to visualize the effect of new viruses on cross-protection by vaccination or past infection, further clinical studies are required.

For the novel variants of SARS-CoV-2, the spike protein is heavily mutated along with the potential mutations in the other genomic sites of the virus [5]. Non-vaccinated individuals, severely ill hospitalized patients as well as the immunocompromised individuals provide more time for a virus to get mutated and develop a more devastatic version of the prominent strain. Now, majority of the EUA vaccines with different platforms are designed considering viral spike proteins; hence, they are not proved to be potentially efficacious against new emerging variants of SARS-CoV-2 [21]. On the other hand, COVID-19-recovered patients are not completely immune for the emerging variants as the neutralizing antibodies generated do not provide complete immune protection though T-cell-mediated immune responses aid in reducing further hospitalizations and severe disease. There are a number of clinical trials published on booster, third and fourth dosing of the vaccine to determine the efficacy against current variants of concern, i.e. omicron as current vaccines do not provide complete immune protection [22,23]. In conclusion, the neutralizing antibodies produced as a result on vaccination or post recovery of COVID-19 are not providing sufficient immune protection against emerging SARS-CoV-2 variants and as such booster doses are recommended. At the present time, omicron variants are surging with BA.4 and BA.5 becoming dominant, and hence designing variant specific vaccines would overcome the rapid waning of the current vaccines and increase antibody cross-reactivity. Enrollment of children and pregnant women shall also be considered in clinical trials design as well as long-term follow-up studies of vaccinated individuals regarding safety profiles and cellular immunity stimulation.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors would like to thank the Immunology and Translational Research Group for their significant contribution. The Mechanisms and Interventions in Health and Disease Program within the Institute for Health and Sport, Victoria University, Australia, are also appreciated for their support. V.A. was supported by a Planetary Health Grant PH098 from Victoria University. V.A. would like to thank the Greek Orthodox Archdiocese of Australia Funds, The Thelma and Paul Constantinou Foundation, The Pappas Family, and the VU Vaccine appeal Funds, whose generous philanthropic support made possible the preparation of this paper. V.P. is grateful to the L.M. College of Pharmacy, Ahmedabad, India, for providing necessary support in carrying out the literature search.

Additional information

Funding

This paper was not funded.