8 research outputs found

    DataSheet_1_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).docx

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    Most if not all vaccine candidates developed to combat COVID-19 due to SARS-CoV-2 infection are administered parenterally. As SARS-CoV-2 is transmitted through infectious respiratory fluids, vaccine-induced mucosal immunity could provide an important contribution to control this pandemic. ChAd-SARS-CoV-2-S (BBV154), a replication-defective chimpanzee adenovirus (ChAd)-vectored intranasal (IN) COVID-19 vaccine candidate, encodes a prefusion-stabilized version of the SARS-CoV-2 spike protein containing two proline substitutions in the S2 subunit. We performed preclinical evaluations of BBV154 in mice, rats, hamsters and rabbits. Repeated dose toxicity studies presented excellent safety profiles in terms of pathology and biochemical analysis. IN administration of BBV154 elicited robust mucosal and systemic humoral immune responses coupled with Th1 cell-mediated immune responses. BBV154 IN vaccination also elicited potent variant (omicron) cross neutralization antibodies. Assessment of anti-vector (ChAd36) neutralizing antibodies following repeated doses of BBV154 IN administration showed insignificant titers of ChAd36 neutralizing antibodies. However, the immune sera derived from the same animals displayed significantly higher levels of SARS-CoV-2 virus neutralization (p<0.003). We also evaluated the safety and immunogenicity of heterologous prime-boost vaccination with intramuscular (IM) COVAXIN-prime followed by BBV154 IN administration. COVAXIN priming followed by BBV154 IN-booster showed an acceptable reactogenicity profile comparable to the homologous COVAXIN/COVAXIN or BBV154/BBV154 vaccination model. Heterologous vaccination of COVAXIN-prime and BBV154 booster also elicited superior (p<0.005) and cross variant (omicron) protective immune responses (p<0.013) compared with the homologous COVAXIN/COVAXIN schedule. BBV154 has successfully completed both homologous and heterologous combination schedules of human phase 3 clinical trials and received the restricted emergency use approval (in those aged above 18 years) from the Drugs Controller General of India (DCGI).</p

    The <i>emrA1</i> mutant vaccinated mice induce sustained production of pro-inflammatory cytokines and a potent antibody response following lethal <i>Ft</i> LVS challenge.

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    <p>C57BL/6 mice immunized i.n. with 1×10<sup>6</sup> CFU of the <i>emrA1</i> mutant were challenged i.n. with 1×10<sup>7</sup> CFU of wild type <i>Ft</i> LVS 42 days post-immunization. <b>(A-D)</b> On days 5, 7 and 14 post-challenge, mice (n = 3 per group/time point) were euthanized and their excised lungs were homogenized. Clear lung homogenates were used for quantification of indicated pro-inflammatory cytokines using flow cytometric analysis. The data are represented as Mean ± S.D. <b>(E)</b> On day 21 post-challenge, mice (n = 3 per group) were anesthetized and bled retroorbitally to obtain serum. <i>Ft</i> specific total IgG, IgG2a, IgG2b, IgG1 and IgA levels in serum samples were determined by ELISA. The data are represented as Mean ± S.D. of absorbance values measured at 450 nm. Red arrows indicate antibody titers. ND = Not detected.</p

    Immunization with <i>emrA1</i> mutant using a prime-boost vaccination regimen improves the extent of protection against <i>Ft</i> SchuS4 challenge.

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    <p><b>(A)</b> C57BL/6 mice (n = 10 per group) were immunized i.n. with 1×10<sup>6</sup> CFU of the <i>emrA1</i> mutant and boosted i.d. on day 21 with a similar dose. On day 42 of the primary immunization mice were challenged i.n. with 17 CFU of <i>Ft</i> SchuS4. Age matched unvaccinated mice challenged with a similar dose of <i>Ft</i> SchuS4 served as controls. <b>(B)</b> C57BL/6 mice (n = 10 per group) were immunized i.d. with 1×10<sup>6</sup> CFU of the <i>emrA1</i> mutant and boosted i.n. on day 21 with a similar dose. On day 42 of the primary immunization mice were challenged i.n. with 17 CFU of <i>Ft</i> SchuS4. Age matched unvaccinated mice challenged with a similar dose of <i>Ft</i> SchuS4 served as controls. The survival results are expressed as Kaplan-Meier survival curves and P values were determined by Log-rank test.</p

    Mice immunized with the <i>emrA1</i> mutant are protected against 1000LD100–10,000LD100 challenge dose of <i>Ft</i> LVS.

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    <p>C57BL/6 mice (n = 5–10 per group) were immunized i.n. with 1×10<sup>6</sup> CFU of the <i>emrA1</i> mutant. <b>(A, B)</b> On day 42 of the primary immunization mice were challenged i.n. with 1×10<sup>7</sup> CFU of wild type <i>Ft</i> LVS. Age matched unvaccinated mice challenged with a similar dose of <i>Ft</i> LVS were kept as controls. (<b>C, D)</b> On day 42 of the primary immunization mice were challenged i.n. with 1×10<sup>8</sup> CFU of wild type <i>Ft</i> LVS. Age matched unvaccinated mice challenged with a similar dose of <i>Ft</i> LVS were kept as controls. (<b>E, F)</b> On day 75 of the primary immunization mice were challenged i.n. with 1×10<sup>7</sup> CFU of wild type <i>Ft</i> LVS. Age matched unvaccinated mice challenged with a similar dose of <i>Ft</i> LVS were kept as controls. The Challenged mice were observed for morbidity and mortality for a period of 21 days post-challenge (<b>A, C, E</b>). The mice were weighed at the indicated times post-challenge to monitor the progression of infection (<b>B, D, F</b>). The survival results are expressed as Kaplan-Meier survival curves and P values were determined by Log-rank test. Body weights of mice are expressed percent body weights.</p

    Immunization with <i>emrA1</i>-mAb complexes improves the extent of protection against <i>Ft</i> SchuS4 challenge.

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    <p><b>(A)</b> C57BL/6 mice (n = 10 per group) immunized i.n. with 1×10<sup>6</sup> CFU of the <i>emrA1</i> mutant-mAb immune complexes. On day 42 of the primary immunization mice were challenged i.n. with 32 CFU of <i>Ft</i> SchuS4. Age matched unvaccinated mice challenged with a similar dose of <i>Ft</i> SchuS4 served as controls. The survival results are expressed as Kaplan-Meier survival curves and P values were determined by Log-rank test. <b>(B)</b> The mice were weighed at the indicated times post-challenge to monitor the progression of infection. <b>(C)</b> The indicated <i>Ft</i> specific antibodies were determined in serum from immunized mice on day 14 post-immunization. The results are expressed as antibody titers.</p

    Immunization with <i>emrA1</i>-mAb complexes using a prime-boost vaccination regimen or a low dose immunization improves the extent of protection against <i>Ft</i> SchuS4 challenge.

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    <p><b>(A)</b> C57BL/6 mice (n = 10 per group) were immunized i.d. with 1×10<sup>6</sup> CFU of the <i>emrA1</i> mutant-mAb immune complex and boosted i.n. on day 21 with a similar dose. On day 42 of the primary immunization mice were challenged i.n. with 17 CFU of <i>Ft</i> SchuS4. Age matched unvaccinated mice challenged with a similar dose of <i>Ft</i> SchuS4 served as controls. <b>(B)</b> C57BL/6 mice (n = 10 per group) immunized i.n. with 1×10<sup>6</sup> CFU of the <i>emrA1</i>mutant-mAb immune complex and boosted i.d. on day 21 with a similar dose. On day 42 of the primary immunization mice were challenged i.n. with 17 CFU of <i>Ft</i> SchuS4. Age matched unvaccinated mice challenged with a similar dose of <i>Ft</i> SchuS4 served as controls. <b>(C)</b> C57BL/6 mice (n = 10 per group) immunized i.n. with 1×10<sup>3</sup> CFU of the <i>emrA1</i> mutant and boosted i.d. on day 21 with a similar dose. On day 42 of the primary immunization mice were challenged i.n. with 17 CFU of <i>Ft</i> SchuS4. Age matched unvaccinated mice challenged with a similar dose of <i>Ft</i> SchuS4 served as controls. <b>(D)</b> C57BL/6 mice (n = 10 per group) immunized i.d. with 1×10<sup>3</sup> CFU of the <i>emrA1</i> mutant and boosted i.n. on day 21 with a similar dose. On day 42 of the primary immunization mice were challenged i.n. with 17 CFU of <i>Ft</i> SchuS4. Age matched unvaccinated mice challenged with a similar dose of <i>Ft</i> SchuS4 served as controls. The survival results are expressed as Kaplan-Meier survival curves and P values were determined by Log-rank test.</p
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