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Introduction: Heterologous vaccines enhance the immune response to new variants and allow flexibility in booster administration when the original vaccine is unavailable. Studies show that heterologous boosters can generate comparable or superior antibody responses compared to homologous boosters. Considering rare side effects is essential in evaluating COVID-19 vaccines, especially those associated with ChAdOx1-S (AstraZeneca) and Ad26.COV2.S (Janssen), including blood clotting and idiopathic thrombocytopenia. Severe side effects, such as myocarditis and pericarditis, may occur after Pfizer or Moderna boosters but are rare. Methods: This study administered two vaccines: the Sinopharm inactivated virus vaccine and the Razi-CoV-Pars (RCP) booster. Various evaluations included biochemical markers, coagulation factors, autoimmune antibodies, and antibodies against concerning variants. Results: All 90 participants exhibited a notable rise in antibody levels against the variant of concern (VOC). Participants receiving the Razi-CoV-Pars booster after Sinopharm/BBIBP-CorV showed significantly higher antibody levels (Wuhan ∼ 3.25 times, Delta ∼4 times, Omicron ∼ 14 times) compared to those receiving Sinopharm's homologous vaccine. No significant changes (P:

Abstract Background The immunity induced by primary vaccination is effective against COVID-19; however, booster vaccines are needed to maintain vaccine-induced immunity and improve protection against emerging variants. Heterologous boosting is believed to result in more robust immune responses. This study investigated the safety and immunogenicity of the Razi Cov Pars vaccine (RCP) as a heterologous booster dose in people primed with Beijing Bio-Institute of Biological Products Coronavirus Vaccine (BBIBP-CorV). Methods We conducted a randomized, double-blind, active-controlled trial in adults aged 18 and over primarily vaccinated with BBIBP-CorV, an inactivated SARS-CoV-2 vaccine. Eligible participants were randomly assigned (1:1) to receive a booster dose of RCP or BBIBP-CorV vaccines. The primary outcome was neutralizing antibody activity measured by a conventional virus neutralization test (cVNT). The secondary efficacy outcomes included specific IgG antibodies against SARS-CoV-2 spike (S1 and receptor-binding domain, RBD) antigens and cell-mediated immunity. We measured humoral antibody responses at 2 weeks (in all participants) and 3 and 6 months (a subgroup of 101 participants) after the booster dose injection. The secondary safety outcomes were solicited and unsolicited immediate, local, and systemic adverse reactions. Results We recruited 483 eligible participants between December 7, 2021, and January 13, 2022. The mean age was 51.9 years, and 68.1% were men. Neutralizing antibody titers increased about 3 (geometric mean fold increase, GMFI = 2.77, 95% CI 2.26–3.39) and 21 (GMFI = 21.51, 95% CI 16.35–28.32) times compared to the baseline in the BBIBP-CorV and the RCP vaccine groups. Geometric mean ratios (GMR) and 95% CI for serum neutralizing antibody titers for RCP compared with BBIBP-CorV on days 14, 90, and 180 were 6.81 (5.32–8.72), 1.77 (1.15–2.72), and 2.37 (1.62–3.47) respectively. We observed a similar pattern for specific antibody responses against S1 and RBD. We detected a rise in gamma interferon (IFN-γ), tumor necrosis factor (TNF-α), and interleukin 2 (IL-2) following stimulation with S antigen, particularly in the RCP group, and the flow cytometry examination showed an increase in the percentage of CD3 + /CD8 + lymphocytes. RCP and BBIBP-CorV had similar safety profiles; we identified no vaccine-related or unrelated deaths. Conclusions BBIBP-CorV and RCP vaccines as booster doses are safe and provide a strong immune response that is more robust when the RCP vaccine is used. Heterologous vaccines are preferred as booster doses. Trial registration This study was registered with the Iranian Registry of Clinical Trial at www.irct.ir , IRCT20201214049709N4. Registered 29 November 2021.

Protective antibodies in the upper respiratory tract prevent the spread of COVID-19 in the community. Intranasal vaccines could raise the specific secretory IgA and IgG levels. This is a single-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and immunogenicity of Razi Cov Pars (RCP) intranasal recombinant protein subunit COVID-19 vaccine as a booster in adults. We compared specific IgG and IgA levels in the intranasal RCP group (n = 97) versus placebo (n = 96) in serum, saliva, and nasal mucosal secretions on days 0 and 14 and reported their Geometric Mean Ratios (GMR) and 95% confidence intervals (CI). We showed significant increases in IgA and IgG anti-RBD in the nasal mucosa in the RCP group, but their increase was not detectable in the serum and saliva. Anti-spike IgA in the nasal mucosa also increased in the RCP group compared to the placebo. This increase against the COVID-19 variant Omicron was also similar to that of the Wuhan. We detected no serious adverse reactions or anaphylaxis and all adverse events resolved completely during the follow-up period and were similar in both groups. Intranasal RCP is safe, stimulates the respiratory mucosal immunity, and could be a booster on various COVID-19 vaccines and be effective against new virus variants.

Background: We conducted a phase III, non-inferiority trial comparing safety and efficacy of RCP recombinant spike protein Covid-19 vaccine to BBIBP (Sinopharm). Methods: Adult Iranian population received RCP or BBIBP in a randomized, double blind and an additional non-randomized open labeled trial arms. Eligible participants signed a written informed consent and received two intramuscular injections three weeks apart. In the randomized arm, an intranasal dose of vaccine or adjuvant-only preparation were given to the RCP and BBIBP recipients at day 51 respectively. Participants were actively followed for up to 4 months for safety and efficacy outcomes. Primary outcome was PCR + symptomatic Covid-19 disease two weeks after the second dose. The non-inferiority margin was 10% of reported BBIBP vaccine efficacy (HR = 1.36). Results: We recruited 23,110 participants (7224 in the randomized and 15,886 in the non-randomized arm). We observed 604 primary outcome events during 4 months of active follow-up including 121 and 133 in the randomized and 157 and 193 cases in the non-randomized arms among recipients of RCP and BBIBP respectively. Adjusted hazard ratios for the primary outcome in those receiving RCP compared with BBIBP interval were 0.91 (0.71–1.16) and 0.62 (0.49–0.77) in the randomized and non-randomized arms respectively. The upper boundary of 99.1% confidence interval of HR = 0.91 (0.67–1.22) remained below the margin of non-inferiority in the randomized arm after observing the early stopping rules using O'Brien Fleming method. Conclusion: Our study showed that the RCP efficacy is non-inferior and its safety profile is comparable to the BBIBP.

Background: Pertussis is still one of the major public health problems. The increase of the disease emerged in recent decades due to the replacement of the reactogenic whole cell vaccine with the safer acellular vaccine and the genetic diversity of the bacterium. As outer membrane vesicles (OMVs) obtained from Bordetella pertussis contains surface immunogenic antigen in its structure, it has an acceptable characteristic that could be considered as a good candidate for pertussis vaccine. Materials & Methods: Vaccinal strain BP134 strain of B. pertussis was cultured under standard conditions and OMVs were isolated by modifying the method without the use of ultracentrifuge. The isolated vesicles were examined by transmission electron microscopy and protein content was measured by the Bradford method. The expression of virulence factors was confirmed by SDS-PAGE and protein expression was confirmed by Western immunoblot. Pyrogenicity test and abnormal toxicity test were performed on extracted vesicles. Results: The morphology of the vesicles was confirmed in the range of 40 to 200 nm. The protein concentration of the extracted vesicles was determined as 600 μg. Expression analysis by SDS-PAGE and western blot confirmed the presence of virulence factors, pertussis toxin, filamentous hemagglutinin, and pertactin using monoclonal antibodies in OMVs of the vaccinal strain. Pyrogenicity test and abnormal toxicity test were negative. Conclusion: The proposed method is a simple and efficient method for isolation of the B. pertussis OMVs. The OMVs extracted from B. pertussis could be a candidate for a new generation of pertussis vaccine alone or in combination with adjuvants to design future acellular vaccines.

Several vaccine candidates for COVID-19 have been developed, and few vaccines received emergency approval with an acceptable level of efficacy and safety. We herein report the development of the first recombinant protein-based vaccine in Iran based on the recombinant SARS-CoV-2 spike protein in its monomeric (encompassing amino acid 1-674 for S1 and 685-1211 for S2 subunits) and trimer form (S-Trimer) formulated in the oil-in-water adjuvant system RAS-01 (Razi Adjuvant System-01). The safety and immunity of the candidate vaccine, referred to as RAZI-COV PARS, were evaluated in Syrian hamster, BALB/c mice, Pirbright guinea pig, and New Zeeland white (NZW) rabbit. All vaccinated animals received two intramuscular (IM) and one intranasal (IN) candidate vaccine at 3-week intervals (days 0, 21, and 51). The challenge study was performed intranasally with 5×106 pfu of SARS-CoV-2 35 days post-vaccination. None of the vaccinated mice, hamsters, guinea pigs, or rabbits showed any changes in general clinical observations; body weight and food intake, clinical indicators, hematology examination, blood chemistry, and pathological examination of vital organs. Safety of vaccine after the administration of single and repeated dose was also established. Three different doses of candidate vaccine stimulated remarkable titers of neutralizing antibodies, S1, Receptor-Binding Domain (RBD), and N-terminal domain (NTD) specific IgG antibodies as well as IgA antibodies compared to placebo and control groups (P

Objectives: This study aimed to determine the safety and immunogenicity of a combined intramuscular/intranasal recombinant spike protein COVID-19 vaccine (RCP). Methods: We conducted a randomized, double-blind, placebo-controlled, phase I trial. Three vaccine strengths were compared with an adjuvant-only preparation. It included two intramuscular and a third intranasal dose. Eligible participants were followed for adverse reactions. Specific IgG, secretory IgA, neutralizing antibodies, and cell-mediated immunity were assessed. Results: A total of 153 participants were enrolled (13 sentinels, 120 randomized, 20 non-randomized open-labeled for IgA assessment). No related serious adverse event was observed. The geometric mean ratios (GMRs) and 95% CI for serum neutralizing antibodies compared with placebo two weeks after the second injection were 5.82 (1.46–23.13), 11.12 (2.74–45.09), and 20.70 (5.05–84.76) in 5, 10, and 20 µg vaccine groups, respectively. The GMR for anti-RBD IgA in mucosal fluid two weeks after the intranasal dose was 23.27 (21.27–25.45) in the 10 µg vaccine group. The humoral responses were sustained for up to five months. All vaccine strengths indicated a strong T-helper 1 response. Conclusion: RCP is safe and creates strong and durable humoral and cellular immunity and good mucosal immune response in its 10 µg /200 µL vaccine strengths. Trial registration: IRCT20201214049709N1.