The coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has already claimed more than 6.8 million lives worldwide. Despite the rapid development and widespread distribution of COVID-19 vaccines, the pandemic persists due to the continual emergence of new SARS-CoV-2 variants.
Study: Immunogenicity and Tolerability of BBV154 (iNCOVACC®), an Intranasal SARS-CoV-2 Vaccine, Compared with Intramuscular Covaxin® in Healthy Adults: A Randomised, Open-Label, Phase 3 Clinical Trial. Image Credit: Dmitry Kovalchuk/Shutterstock
*Important notice: Preprints with The Lancet / SSRN publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Some of these variants, such as the Delta and Omicron variants of concern (VOCs), can evade the immune response induced by vaccination or natural infection. Therefore, scientists are looking to improve current vaccine formulations to provide better protection against SARS-CoV-2 infection.
Background
Most COVID-19 vaccines target the spike protein of the ancestral SARS-CoV-2 strain. Due to the presence of numerous mutations on SARS-CoV-2 variant spike proteins, the efficacy of these vaccines has been significantly reduced.
SARS-CoV-2 must overcome both anatomical and immunological barriers presented by the nasal mucosa to establish infection. Mucosal immunity has a crucial role in blocking SARS-CoV-2 infection to prevent its transmission; however, all currently available COVID-19 intramuscular vaccines primarily elicit systemic immunity, with a limited impact on mucosal immunity.
An effective intranasal vaccine could be extremely beneficial in managing the COVID-19 pandemic by eliciting both mucosal protective immunity at the site of infection and systemic immunity. Recently, Bharat Biotech International Limited (BBIL) in India has developed BBV154. BBV154 is a chimpanzee adenoviral-vectored SARS-CoV-2 intranasal vaccine that encodes a prefusion-stabilized SARS-CoV-2 wild-type spike protein with two proline substitutions in the S2 subunit.
Preclinical animal studies on mice, hamsters, rabbits, and rats have revealed that BBV154 induces strong mucosal and systemic humoral and cell-mediated immune responses.
In fact, a single intranasal dose of BBV154 elicited a superior immune response in highly susceptible K18-hACE2 99 transgenic mice as compared to the same doses of COVID-19 intramuscular vaccines. Furthermore, a single intranasal dose BBV154 in Syrian golden hamsters, K18-hACE2 transgenic mice, and rhesus macaques prevented the development of upper and lower respiratory tract infections and inflammation due to COVID-19.
About the study
A recent preprint study published by The Lancet discusses the safety profiles and immunogenicity of BBV154 in healthy adults. These findings are based on results from a Phase III, randomized, controlled, open-label clinical trial that was conducted across hospitals in India.
The authors assessed the safety, tolerability, and immunogenicity of BBV154 in healthy adults, which included males and non-pregnant women, in addition to comparing the efficacy of this vaccine with the licensed intramuscular vaccine, Covaxin.
All study participants were between 18 and 60 years of age at the time of recruitment. None of the study participants previously received any COVID-19 vaccine or had a history of SARS-CoV-2 infection.
Study findings
A total of 3,209 participants were recruited between April 16, 2022, and June 4, 2022, 2,998 of whom were randomized to receive BBV154 and 162 to receive Covaxin.
Neutralization titers against the ancestral SARS-CoV-2 strain induced after two weeks of receiving the second dose of the intranasal BBV154 vaccine were significantly higher as compared to those produced in Covaxin recipients under similar conditions.
Neutralization antibodies were also detected three months after the first dose of the BBV154 vaccine, thus confirming its durability. The intranasal vaccine also elicited increased cross-neutralization titers against the Omicron variant BA.5 sub-lineage.
Robust mucosal antibodies in the form of secretory immunoglobulin A (sIgA) were also detected in participants who received the BBV154 vaccine on Day 42. The levels of sIgA in the BBV154 group were much higher as compared to the Covaxin group. This finding was validated based on the presence of statistically significant IgA-secreting plasmablasts in the BBV154 group on Day 42 as compared with Day 0.
Both types of COVID-19 vaccines were well tolerated with low reactogenicity rates. None of the participants reported any serious adverse effects following vaccination.
For respiratory infections, mucosal immunization is associated with several advantages as compared to conventional intramuscular vaccination. For example, mucosal IgA protects mucosal surfaces against respiratory viruses by inhibiting their attachment to epithelial cells. Previous studies on influenza infection have revealed that influenza-specific IgA is more effective in preventing infection in humans than influenza-specific IgG.
SARS-CoV-2 initially infects the upper respiratory tract, which leads to an increase in plasma IgA antibody levels that bind to the virus and prevent infection. This highlights the crucial role of IgA-mediated mucosal immunity against COVID-19.
IgA dimers found in the nasopharynx are significantly more potent than IgA monomers against the same target. Therefore, secretory (dimeric) IgA could be more effective in protecting against SARS-CoV-2 infection.
Conclusions
The BBV154 intranasal vaccine was found to be superior to the intramuscular Covaxin vaccine, as BBV154 induces higher levels of IgG/IgA-secreting plasmablasts that correlate with increased neutralization potency against homologous and heterologous SARS-CoV-2 strains.
Some of the key advantages of BBV154 include its non-invasiveness, ease of administration, improved patient compliance, and fitness for mass vaccination. Currently, further clinical development of BBV154 is undergoing as a part of a heterologous booster vaccination regime.
*Important notice: Preprints with The Lancet / SSRN publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Journal reference:
- Preliminary scientific report.
Singh, C., Verma, S., Reddy, P., et al. (2023) Immunogenicity and Tolerability of BBV154 (iNCOVACC®), an Intranasal SARS-CoV-2 Vaccine, Compared with Intramuscular Covaxin® in Healthy Adults: A Randomised, Open-Label, Phase 3 Clinical Trial. Preprints with the Lancet. doi:10.2139/ssrn.4342771.
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