Phase III Pivotal comparative clinical trial of intranasal (iNCOVACC) and intramuscular COVID 19 vaccine (Covaxin®)

COVID-19, caused by the SARS-CoV-2 virus, a mucosal pathogen, emerged as a global pandemic. While first-generation vaccines effectively mitigated its impact, the ongoing evolution of new variants necessitates further solutions (1, 2).
Published in Biomedical Research
Phase III Pivotal comparative clinical trial of intranasal (iNCOVACC) and intramuscular COVID 19 vaccine (Covaxin®)

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Mucosal immunity, one of the important component of the entire immune system, induces extensive adaptive immune responses, involving secretory IgA as the dominant antibody and tissue resident memory T (TRM) cells, evolved to provide protection at the site of infection against mucosal pathogens (3). As SARS-CoV-2 initially infects the upper respiratory tract, its first interactions with the immune system must occur predominantly at the respiratory mucosal surfaces to facilitate adaptive immunity. Hence, it necessiates the need of second generation vaccines aiming to elicit both mucosal and systemic immunity (4).

 The question is whether we can overcome this limitation using an unconventional, intranasal vaccine, as one of the approaches to develop mucosal responses, which possibly be the future hope, to combat transmission of SARS-CoV-2 variants. Understanding the importance of mucosal vaccines, Bharat Biotech International Limited (BBIL) entered into an agreement with Washington University School of Medicine in St. Louis, USA, for the large scale manufacturing of intranasal COVID-19 vaccine, named as iNCOVACC (BBV154).

 Michael S. Diamond, MD, PhD (The Inventor), the Herbert S. Gasser (Co-Inventor), David T. Curiel, MD, PhD, and their team, at Washington University School of Medicine, inserted the spike protein of SARS-CoV-2 into a virus that causes the common cold, called an adenovirus, which was genetically modified in such a way that it does not cause illness. The harmless adenovirus carries the spike protein into the nose, enable the body to mount an immune response against the SARS-CoV-2 virus without becoming sick. Further, incorporation of two mutations into the spike protein stabilizes its specific shape that is most conducive to form antibodies against it. Both innovations were designed not only to improve the ease of production, but also to elicit a strong immune response against spike protein (5). Thus, the vaccine, iNCOVACC (BBV154) is a novel chimpanzee-adenovirus (simian Ad-36)-based SARS-CoV-2 vaccine (ChAd36-SARS-CoV-2-S) was designed.

 Subsequently, BBIL took over the vaccine development and manufactured BBV154 vaccine in large scale and formulated for Intranasal administration as drops in a refined delivery device. The vaccine is administered as drops and is specially suitable for large scale immunization campaigns in a cost-effective manner. A dedicated team of highly qualified professionals with interdisciplinary experience worked relentlessly to produce vaccine at commercial scale and established quality control assays in short time, when the limited logistics were available during pandemic situation.

 This was a race against the time with limited resources since BBIL was the only company which was working to develop two fully licensed, Covid-19 vaccines. Our Teams ensured that no short-cuts were adopted and comprehensive characterization of the vaccines were completed before routine human usage.

 Early studies done by Michael S Diamond group were encouraging and gave a hope for further scale up. A single intranasal (IN) dose of ChAd36-SARS-CoV-2-S conferred superior protective immunity against SARS-CoV-2 virus challenge in mice than one or two intramuscular (IM) doses of the same vaccine. Additionally, one IN dose of ChAd36-SARS-CoV-2-S prevented upper and lower respiratory tract infection and inflammation by SARS-CoV-2 in highly susceptible K18-hACE2 transgenic mice and Syrian hamsters (5, 6), with similar results in rhesus macaques (7).

 Further, excellent safety profile of BBV154 IN vaccination demonstrated in Preclinical studies (mice, rats, hamsters & NZW Rabbits conducted at BBIL), coupled with broad and robust mucosal, systemic humoral and cell-mediated immune responses (8) reassured the effectiveness of this vaccine to conduct clinical trials.

 BBIL conducted several clinical trials to evaluate the safety and immunogenicity of the vaccine. This manuscript reports the one of the largest clinical trial, conducted in India, covering various geographical regions, to evaluate the safety and immunogenicity of BBV154, while assessing the lot to lot consistency.

 In addition, homologous and heterologous vaccination combinations using BBV154 & COVAXIN were evaluated for the better outcome of immune responses, as the initial roll out of Covid-19 vaccination has already been implemented in several countries. COVAXIN priming followed by BBV154 IN-booster not only showed an acceptable reactogenicity profile but also elicited superior and cross variant (omicron) protective immune responses compared with the homologous schedules.

 Antigen specific Secretory as well as circulating IgA antibodies play a significant role in mucosal immunity and hence elucidation of Secretory and systemic IgA antibody levels were exploited along with neutralization antibody titers and CMI responses, to assess the beneficial effects of intranasal COVID-19 vaccine, that helps to prevent or block transmission. In this study, BBV154 induced higher Salivary IgA titers, which were further corraborated by the  significant levels of ancestral specific IgA-secreting plasmablasts, post vaccination. Moreover, BBV154 induced serum neutralization antibody titers against the ancestral (Wuhan) virus, were met the pre-defined superiority criterion over Covaxin®.

 Today, iNCOVACC is the world’s first nasal vaccine for COVID-19, fully approved by Drugs Controller General of India (DCGI) on Tuesday, Sept. 6, 2022, for emergency use both in primary schedule as two doses and as a booster dose post vaccination with other vaccines.

 This study entitled “Phase III Pivotal comparative clinical trial of intranasal (iNCOVACC) and intramuscular COVID 19 vaccine (Covaxin®)”, has been published in npj Vaccines 8, 125 (2023).


  1. Dhama K, Dhawan M, Tiwari R, Emran TB, Mitra S, Rabaan AA, Alhumaid S, Alawi ZA, Al Mutair A. COVID-19 intranasal vaccines: current progress, advantages, prospects, and challenges. Hum Vaccin Immunother. 2022 Nov 30;18(5):2045853. doi: 10.1080/21645515.2022.2045853. Epub 2022 Mar 8. PMID: 35258416; PMCID: PMC8935456. 
  1. qu Alu, Li Chen, Hong Lei, Yuquan Wei, Xiaohe Tian, Xiawei Wei. Intranasal COVID-19 vaccines: From bench to bed. eBioMedicine, Volume 76, 2022, 103841, ISSN 2352-3964. 
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  1. Russell MW, Moldoveanu Z, Ogra PL and Mestecky J (2020) Mucosal Immunity in COVID-19: A Neglected but Critical Aspect of SARS-CoV-2 Infection. Front. Immunol. 11:611337. doi: 10.3389/fimmu.2020.611337 
  1. Hassan AO, Kafai NM, Dmitriev IP, Fox JM, Smith BK, Harvey IB, et al. A single-dose intranasal ChAd vaccine protects upper and lower respiratory tracts against SARS-CoV-2. Cell (2020) 183:169–184.e113. doi: 10.1016/j.cell.2020.08.026 
  1. Bricker TL, Darling TL, Hassan AO, Harastani HH, Soung A, Jiang X, et al. A single intranasal or intramuscular immunization with chimpanzee adenovirus vectored SARS-CoV-2 vaccine protects against pneumonia in hamsters. Cell Rep (2021) 36(3):109400. doi: 10.1016/j.celrep.2021.109400 
  1. Hassan AO, Feldmann F, Zhao H, Curiel DT, Okumura A, Tang-Huau TL, et al. A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques. Cell Rep Med (2021) 2 (4):100230. doi: 10.1016/j.xcrm.2021.100230 
  1. Sunagar R, Prasad SD, Ella R and Vadrevu KM (2022) Preclinical evaluation of safety and immunogenicity of a primary series intranasal COVID-19 vaccine candidate (BBV154) and humoral immunogenicity evaluation of a heterologous prime-boost strategy with COVAXIN (BBV152). Front. Immunol. 13:1063679. doi: 10.3389/fimmu.2022.1063679


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