Currently, there are 9 approved vaccines against SARS-CoV-2 virus that are used to prevent transmission, and prevent hospitalisation and deaths. However, all vaccines are given intramuscularly and appear to induce systemic protective immunity and not sterile immunity, and carry minor side effects. Current vaccines predominantly induce IgG antibody response and very little IgA responses. IgA is a predominant protective antibody in the nose and pharynx.

In natural Covid-19 infection, both IgG and IgA responses are induced. This is one of the reasons why after full vaccination some individuals, though rare, are still susceptible to SARS-CoV-2 infection. Taking into consideration current status of repeated surges and mutations in SARS-CoV-2, it is likely that this virus would be with us for some time. We also do not know how long vaccine-induced immunity would last.  Therefore, we may require booster vaccines and modified vaccines to overcome mutant strains.

Furthermore, there is a hesitation in getting injectable vaccines, and then there are problems with storage and shelf life of vaccines. Thus, there is a need to develop vaccines that are not only directed against spike protein where most mutations occur, but directed against other viral proteins that are not susceptible to mutations, for example nucleocapsid and membrane proteins. In addition, there is a need to develop vaccines that may be administered by alternative routes including orally, inhalation, and under the skin. A number of such vaccines are in Phase I trial to determine safety. If proven safe, these vaccines will undergo phase II and phase III clinical trials to determine effectiveness of the vaccine. UB-612 multitope peptide-based vaccine (COVAXX; developed by United Biomedical, Inc) is composed of SARS-CoV-2 amino acid sequences of the receptor binding domain.

Further formulated with designer Th and CTL epitope peptides derived from the S2 subunit, membrane, and nucleoprotein regions of SARS-CoV-2 structural proteins for induction of memory recall, T-cell activation, and effector functions against SARS-CoV-2. In Taiwan, phase 2 trial, and phase 2/3 trial in Brazil have started. Altimmune, Inc has developed intranasal COVID-19 vaccine (AdCOVID). It is a single-dose vaccine. Preclinical results showed stimulation of antigen-specific CD4+ and CD8+ T-cells in mildly affected lungs as early as 10th day. Phase 1 safety and immunogenicity study has begun in Q4 2020. University of Oxford, UK has developed ChAdOx1 nCov-19 inhaled vaccine. 

Dose-ranging trial for orally inhaled vaccine phase 1 trials in 30 volunteers has started. Self-amplified (saRNA) synthetic inhaled vaccine is developed at Imperial College of London. VXA-CoV2-1 is an oral vaccine (Vaxart). Recombinant adenovirus vector type 5 (Ad5) expressing coronavirus antigen and a toll-like receptor 3 (TLR3) agonist as an adjuvant is used. Preliminary phase 1 trial in a large number of subjects, vaccine induced CD8 T-cell responses to the viral spike protein. Neutralising antibodies not detected in most subjects. Company is evaluating an optimal dosing schedule in order to assess efficacy in phase 2 trials. The PittCoVacc Covid-19 vaccine has been developed by two scientists at University of Pittsburgh School of Medicine, Pittsburg, PA. Vaccine candidate using transdermal micro-needle for Covid-19. In mice, vaccines produced antibodies over a 2-wk period; micro-needles are made of sugar, making it easy to mass-produce and store without refrigeration.

In near future, we can expect many more vaccines targeted against multiple components of SARS-CoV-2 to be delivered by convenient oral and inhaled routes that would be effective against expanding mutant strains.

The writer is Professor of Medicine, University of California, Irvine, California, USA.

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