Systemic immune profiling of Omicron-infected subjects inoculated with different doses of inactivated virus vaccine.

SARS-CoV-2 primary strain-based vaccination exerts a protective effect against Omicron variants-initiated infection, symptom occurrence, and disease severity in a booster-dependent manner. Yet, the underlying mechanisms remain unclear. During the 2022 Omicron outbreak in Shanghai, we enrolled 122 infected adults and 50 uninfected controls who had been unvaccinated or vaccinated with two or three doses of COVID-19 inactive vaccines and performed integrative analysis of 41-plex CyTOF, RNA-seq, and Olink on their peripheral blood samples. The frequencies of HLA-DRhi classical monocytes, non-classical monocytes, and Th1-like Tem tended to increase, whereas the frequency of Treg was reduced by booster vaccine, and they influenced symptom occurrence in a vaccine dose-dependent manner. Intercorrelation and mechanistic analysis suggested that the booster vaccination induced monocytic training, which would prime monocytic activation and maturation rather than differentiating into myeloid-derived suppressive cells upon Omicron infections. Overall, our study provides insights into how booster vaccination elaborates protective immunity across SARS-CoV-2 variants.

Boosting with variant-matched or historical mRNA vaccines protects against Omicron infection in mice.

The large number of spike substitutions in Omicron lineage variants (BA.1, BA.1.1., and BA.2) could jeopardize the efficacy of SARS-CoV-2 vaccines. We evaluated in mice the protective efficacy of the Moderna mRNA-1273 vaccine against BA.1 before or after boosting. Whereas two doses of mRNA-1273 vaccine induced high levels of neutralizing antibodies against historical WA1/2020 strains, lower levels against BA.1 were associated with breakthrough infection and inflammation in the lungs. A primary vaccination series with mRNA-1273.529, an Omicron-matched vaccine, potently neutralized BA.1 but inhibited historical or other SARS-CoV-2 variants less effectively. However, boosting with either mRNA-1273 or mRNA-1273.529 vaccines increased neutralizing titers and protection against BA.1 and BA.2 infection. Nonetheless, the neutralizing antibody titers were higher, and lung viral burden and cytokines were slightly lower in mice boosted with mRNA-1273.529 and challenged with BA.1. Thus, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against Omicron infection with limited differences in efficacy measured.

Interval between prior SARS-CoV-2 infection and booster vaccination impacts magnitude and quality of antibody and B cell responses.

SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a 2-month period, we evaluated antibody and B cell responses to a third-dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies and memory B cells. Spike-specific B cell responses from recent infection (<180 days) were elevated at pre-boost but comparatively less so at 60 days post-boost compared with uninfected individuals, and these differences were linked to baseline frequencies of CD27lo B cells. Day 60 to baseline ratio of BCR signaling measured by phosphorylation of Syk was inversely correlated to days between infection and vaccination. Thus, B cell responses to booster vaccines are impeded by recent infection.

Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine.

We examined antibody and memory B cell responses longitudinally for ∼9-10 months after primary 2-dose SARS-CoV-2 mRNA vaccination and 3 months after a 3rd dose. Antibody decay stabilized between 6 and 9 months, and antibody quality continued to improve for at least 9 months after 2-dose vaccination. Spike- and RBD-specific memory B cells remained durable over time, and 40%-50% of RBD-specific memory B cells simultaneously bound the Alpha, Beta, Delta, and Omicron variants. Omicron-binding memory B cells were efficiently reactivated by a 3rd dose of wild-type vaccine and correlated with the corresponding increase in neutralizing antibody titers. In contrast, pre-3rd dose antibody titers inversely correlated with the fold-change of antibody boosting, suggesting that high levels of circulating antibodies may limit the added protection afforded by repeat short interval boosting. These data provide insight into the quantity and quality of mRNA-vaccine-induced immunity over time through 3 or more antigen exposures.

SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition.

A recombinant lineage of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryoelectron microscopy (cryo-EM) structures of XBB.1.5, XBB.1.16, EG.5, and EG.5.1 spike (S) ectodomains to reveal reinforced 3-receptor binding domain (RBD)-down receptor-inaccessible closed states mediated by interprotomer RBD interactions previously observed in BA.1 and BA.2. Improved XBB.1.5 and XBB.1.16 RBD stability compensated for stability loss caused by early Omicron mutations, while the F456L substitution reduced EG.5 RBD stability. S1 subunit mutations had long-range impacts on conformation and epitope presentation in the S2 subunit. Our results reveal continued S protein evolution via simultaneous optimization of multiple parameters, including stability, receptor binding, and immune evasion, and the dramatic effects of relatively few residue substitutions in altering the S protein conformational landscape.

Proteomic and Cellular Characterization of Omicron Breakthrough Infections and a Third Homologous or Heterologous Boosting Vaccination in a Longitudinal Cohort.

The understanding of dynamic plasma proteome features in hybrid immunity and breakthrough infection is limited. A deeper understanding of the immune differences between heterologous and homologous immunization could assist in the future establishment of vaccination strategies. In this study, 40 participants who received a third dose of either a homologous BBIBP-CorV or a heterologous ZF2001 protein subunit vaccine following two doses of inactivated coronavirus disease 2019 vaccines and 12 patients with BA2.2 breakthrough infections were enrolled. Serum samples were collected at days 0, 28, and 180 following the boosting vaccination and breakthrough and then analyzed using neutralizing antibody tests and mass spectrometer-based proteomics. Mass cytometry of peripheral blood mononuclear cell samples was also performed in this cohort. The chemokine signaling pathway and humoral response markers (IgG2 and IgG3) associated with infection were found to be upregulated in breakthrough infections compared to vaccination-induced immunity. Elevated expression of IGKV, IGHV, IL-17 signaling, and the phagocytosis pathway, along with lower expression of FGL2, were correlated with higher antibody levels in the boosting vaccination groups. The MAPK signaling pathway and Fc gamma R-mediated phagocytosis were more enriched in the heterologous immunization groups than in the homologous immunization groups. Breakthrough infections can trigger more intensive inflammatory chemokine responses than vaccination. T-cell and innate immune activation have been shown to be closely related to enhanced antibody levels after vaccination and therefore might be potential targets for vaccine adjuvant design.

Reminders, but not monetary incentives, increase COVID-19 booster uptake.

Despite substantially decreasing the risk of hospitalization and death from COVID-19, COVID-19 booster vaccination rates remain low around the world. A key question for public health agencies is how to increase booster vaccination rates, particularly among high-risk groups. We conducted a large preregistered randomized controlled trial (with 57,893 study subjects) in a county health system in northern California to test the impact of personal reminder messages and small financial incentives of $25 on booster vaccination rates. We found that reminders increased booster vaccination rates within 2 wk by 0.86 percentage points (P = 0.000) or nearly 33% off the control mean of 2.65%. Monetary incentives had no additional impact on vaccination rates. The results highlight the potential of low-cost targeted messages, but not small financial incentives, to increase booster vaccination rates.

Mechanistic model for booster doses effectiveness in healthy, cancer, and immunosuppressed patients infected with SARS-CoV-2.

SARS-CoV-2 vaccines are effective at limiting disease severity, but effectiveness is lower among patients with cancer or immunosuppression. Effectiveness wanes with time and varies by vaccine type. Moreover, previously prescribed vaccines were based on the ancestral SARS-CoV-2 spike-protein that emerging variants may evade. Here, we describe a mechanistic mathematical model for vaccination-induced immunity. We validate it with available clinical data and use it to simulate the effectiveness of vaccines against viral variants with lower antigenicity, increased virulence, or enhanced cell binding for various vaccine platforms. The analysis includes the omicron variant as well as hypothetical future variants with even greater immune evasion of vaccine-induced antibodies and addresses the potential benefits of the new bivalent vaccines. We further account for concurrent cancer or underlying immunosuppression. The model confirms enhanced immunogenicity following booster vaccination in immunosuppressed patients but predicts ongoing booster requirements for these individuals to maintain protection. We further studied the impact of variants on immunosuppressed individuals as a function of the interval between multiple booster doses. Our model suggests possible strategies for future vaccinations and suggests tailored strategies for high-risk groups.

Vaccine effects on COVID-19 infection with bivalent boosting by age group.

This paper examines time-series vaccine effectiveness on COVID-19 infection with/without a bivalent booster dose by 6 age groups such as 18-29, 30-49, 50-64, 65-79, 80+, and all_ages respectively. CDC's COVID data on rates of COVID-19 cases and deaths by updated (bivalent) booster status was used in this study. This result concludes that there is no difference between vaccines with or without a bivalent booster dose for preventing COVID-19 infection in 6 age groups 18-29, 30-49, 50-64, 65-79, 80+, and all_ages. Vaccination is effective in two age groups of 65-79 and 80+ for preventing COVID-19 infection. However, vaccine effectiveness against COVID-19 infection has not been confirmed in the 18-29 and 30-49 age groups.

Integrating a Biomineralized Nanocluster for H2S-Sensitized ROS Bomb against Breast Cancer.

Nanomaterial-assisted chemodynamic therapy (CDT) has received considerable attention in recent years. It outperforms other modalities by its distinctive reactive oxygen species (ROS) generation through a nonexogenous stimulant. However, CDT is limited by the insufficient content of endogenous hydrogen peroxide (H2O2). Herein, a biodegradable MnS@HA-DOX nanocluster (MnS@HA-DOX NC) was constructed by in situ biomineralization from hyaluronic acid, to enlarge the ROS cascade and boost Mn2+-based CDT. The acid-responsive NCs could quickly degrade after internalization into endo/lysosomes, releasing Mn2+, H2S gas, and anticancer drug doxorubicin (DOX). The Fenton-like reaction catalyzed by Mn2+ was amplified by both H2S and DOX, producing a mass of cytotoxic ·OH radicals. Through the combined action of gas therapy (GT), CDT, and chemotherapy, oxidative stress would be synergistically enhanced, inducing irreversible DNA damage and cell cycle arrest, eventually resulting in cancer cell apoptosis.

What is the economic benefit of annual COVID-19 vaccination from the adult individual perspective?

BACKGROUND: With COVID-19 vaccination no longer mandated by many businesses/organizations, it is now up to individuals to decide whether to get any new boosters/updated vaccines going forward. METHODS: We developed a Markov model representing the potential clinical/economic outcomes from an individual perspective in the United States of getting versus not getting an annual COVID-19 vaccine. RESULTS: For an 18-49-year-old, getting vaccinated at its current price ($60) can save the individual on average $30-$603 if the individual is uninsured and $4-$437 if the individual has private insurance, as long as the starting vaccine efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is ≥50% and the weekly risk of getting infected is ≥0.2%, corresponding to an individual interacting with 9 other people in a day under Winter 2023-2024 Omicron SARS-CoV-2 variant conditions with an average infection prevalence of 10%. For a 50-64-year-old, these cost-savings increase to $111-$1,278 and $119-$1,706, for someone without and with insurance, respectively. The risk threshold increases to ≥0.4% (interacting with 19 people/day), when the individual has 13.4% pre-existing protection against infection (e.g., vaccinated 9 months earlier). CONCLUSION: There is both clinical and economic incentive for the individual to continue to get vaccinated against COVID-19 each year.

Impact of Nutritional Status on Antibody Titer After Booster mRNA COVID-19 Vaccine Among Elderly Adults in Japan.

BACKGROUND: Published studies on mRNA coronavirus disease 2019 (COVID-19) vaccine effects focus on younger individuals, comprising the majority of the workforce. Studies in elderly adults are sparse. METHODS: In total, 107 subjects were recruited (median age 78; interquartile range [IQR], 58.5-90.5; range, 35-105 years). Factors associated with antibody titer after the third mRNA COVID-19 vaccination were compared between 49 elderly (age ≥80; median, 94; IQR, 86-97; range, 80-105 years) and 58 younger (age ≤79; median, 61; IQR, 46-71; range, 35-79 years) adults. RESULTS: Among body mass index (BMI) categories, the group of underweight elderly adults had a lower antibody titer compared to those with normal weight (P < .01 after 1, 3, and 5 months). Elderly adults were less likely to maintain effective antibody titer (≥4160 AU/mL) compared to younger adults: 76% versus 98%, P < .001 after 1 month, and 45% versus 78%, P < .001 after 3 months. Elderly adults who maintained effective antibody titer for 5 months had a higher BMI (22.9 kg/m2 vs 20.1 kg/m2, P = .02), and were less likely to have underweight BMI (0% vs 31%, P = .02) compared to the subjects who failed to maintain effective antibody titer. CONCLUSIONS: These results highlight the impact of nutritional status and the deleterious effect of underweight BMI on antibody titer and its maintenance among elderly adults following booster mRNA COVID-19 vaccination.

An Observational Prospective Cohort Study of Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection of an Aerosolized, Inhaled Adenovirus Type 5-Vectored Coronavirus Disease 2019 Vaccine Given as a Second Booster Dose in Guangzhou City, China.

Using a prospective, observational cohort study during the post-"dynamic COVID-zero" wave in China, we estimated short-term relative effectiveness against Omicron BA.5 infection of inhaled aerosolized adenovirus type 5-vectored ancestral strain coronavirus disease 2019 (COVID-19) vaccine as a second booster dose approximately 1 year after homologous boosted primary series of inactivated COVID-19 vaccine compared with no second booster. Participants reported nucleic acid or antigen test results weekly until they tested positive or completed predesignated follow-up. After excluding participants infected <14 days after study entry, relative effectiveness among the 6576 participants was 61% in 18- to 59-year-olds and 38% in ≥60-year-olds and was sustained for 12 weeks.

Longitudinal analysis of nursing home residents' T cell responses after SARS-CoV-2 mRNA vaccinations shows influence of biological sex and SARS-CoV-2 infection history.

BACKGROUND: Vaccines and vaccine boosting have blunted excess morbidity and mortality from SARS-CoV-2 infection suffered by older nursing home residents (NHR). However, the impact of repeated vaccination on the T cell response based on biological sex and prior infection of NHR remain understudied. METHODS: We examined T cell responses to mRNA vaccines to SARS-CoV-2 in a cohort of NHR and healthcare workers (HCW) over 2 years. We used IFN-γ ELIspot and flow cytometry to assess T cell response before, two weeks and 6 months after the initial series and each of two booster vaccines. We analyzed these data longitudinally with mixed-effect modeling and also examined subsets of our cohorts for additional changes in T cell effector function. RESULTS: We show that prior SARS-CoV-2 infection and female sex contribute to higher T cell response in NHR but not HCW. When looking across time points, NHR but not HCW with prior infection had significantly higher T cell responses than infection-naive subjects. These patterns of response were maintained across multiple booster vaccinations and suggest that the age, multimorbidity, and/or frailty of the NHR cohort may accentuate sex and infection status differences in T cell response to mRNA vaccination.

Informing the Need for a SARS-CoV-2 Booster Based Upon the Immune Responses among Young Healthy Adults to Variants Circulating in Late 2023.

BACKGROUND: COVID-19 remains a global public health challenge due to new immune-evasive SARS-CoV-2 variants and heterogeneous immunity. METHODS: In this cross-sectional study, we evaluated the adaptive immune responses in U.S. active-duty personnel who completed a COVID-19 primary vaccine series and with heterogenous SARS-CoV-2 vaccination and infection histories to 3 previously dominant variants (Ancestral, Delta, BA.5) and 3 circulating variants (XBB.1.5, EG.5, and BA.2.86) in late 2023. Analyses were performed based upon timing (within or beyond 12 months) and type (vaccine or infection) of the most recent exposure. RESULTS: Significant reduction was observed in binding antibodies, neutralization antibodies, memory B cells, and CD8+ T cells against circulating variants compared to previous variants. The reduction in antibody response was more pronounced in those whose most recent exposure was greater than 12 months from enrollment. In contrast, the CD4+ T cell response was largely consistent across all tested variants. The type of most recent exposure was not a significant factor in determining the magnitude of current immune responses. CONCLUSIONS: Administration of the XBB.1.5-based booster is likely to enhance cross-reactive humoral responses against SARS-CoV-2 circulating lineages. Ongoing surveillance of immune responses to emerging variants is needed for informing vaccine composition and timing.

Risks of SARS-CoV-2 JN.1 infection and COVID-19 associated emergency-department (ED) visits/hospitalizations following updated boosters and prior infection: a population-based cohort study.

INTRODUCTION: Data on protection afforded by updated COVID-19 vaccines (bivalent/XBB 1.5 monovalent) against the emergent JN.1 variant remains limited. METHODS: We conducted a retrospective population-based cohort study amongst all boosted Singaporeans aged ≥18 years during a COVID-19 wave predominantly driven by JN.1, from 26th November 2023 to 13th January 2024. Multivariable Cox regression was utilised to assess risk of SARS-CoV-2 infection and COVID-19 associated emergency-department (ED) visits/hospitalizations, stratified by vaccination status/prior infection; with individuals last boosted ≥1 year utilized as the reference category. Vaccination and infection status were classified using national registries. RESULTS: 3,086,562 boosted adult Singaporeans were included in the study population, accounting for 146,863,476 person-days of observation. During the JN.1 outbreak, 28,160 SARS-CoV-2 infections were recorded, with 2,926 hospitalizations and 3,747 ED-visits. Compared with individuals last boosted ≥1 year prior with ancestral monovalent vaccines, receipt of an updated XBB.1.5 booster 8-120 days prior was associated with lower risk of JN.1 infection (adjusted-hazard-ratio, aHR = 0.59[0.52-0.66]), COVID-19 associated ED-visits (aHR = 0.50[0.34-0.73]) and hospitalizations(aHR = 0.58[0.37-0.91]), while receipt of a bivalent booster 121-365 days prior was associated with lower risk of JN.1 infection (aHR = 0.92[0.88-0.95]) and ED-visits (aHR = 0.80[0.70-0.90]). Lower risk of COVID-19 hospitalization during the JN.1 outbreak (aHR = 0.57[0.33-0.97]) was still observed following receipt of an updated XBB.1.5 booster 8-120 days prior, even when analysis was restricted to previously infected individuals. CONCLUSION: Recent receipt of updated boosters conferred protection against SARS-CoV-2 infection and ED-visits/hospitalization during a JN.1 variant wave, in both previously infected and uninfected individuals. Annual booster doses confer protection during COVID-19 endemicity.

Assessing clinical benefits of live-attenuated vaccination in post-liver transplant patients: Analysis of breakthrough infections and natural boosters.

Recently, live-attenuated measles, rubella, varicella, and mumps vaccines have been administered to carefully selected post-liver transplant patients. Although attention has been focused on post-vaccination antibody titers and adverse events, the real-life clinical benefits remain unclear. A comprehensive analysis of breakthrough infections and natural boosters (asymptomatic cases with significant elevation in virus antibody titers) following immunization post-liver transplantation was conducted from 2002-2023, exploring the timing, frequency, correlation with domestic outbreaks, and degree of antibody elevation. During the median 10-year observation period among 68 post-liver transplant patients, breakthrough infections occurred only in chickenpox, with 7 mild cases (1 episode/64 person-years). A total of 59 natural booster episodes (1, 5, 20, and 33 for measles, rubella, chickenpox, and mumps, respectively) were observed, with incidence rates of 1 per 569, 110, 22, and 17 person-years, respectively. The timing of natural boosters closely correlated with domestic outbreaks (P < .05 in chickenpox and mumps), influenced by local vaccine coverage. The degree of antibody elevation was significantly higher in individuals with breakthrough infections than in those with natural boosters (P < .05). These findings suggest that immunization with live-attenuated vaccines for post-liver transplant patients has demonstrated clinical benefits. Furthermore, mass vaccination has a positive impact on post-transplant patient outcomes.

Longitudinal outcomes of COVID-19 in solid organ transplant recipients from 2020 to 2023.

Data regarding coronavirus disease 2019 (COVID-19) outcomes in solid organ transplant recipients (SOTr) across severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) waves, including the impact of different measures, are lacking. This cohort study, conducted from March 2020 to May 2023 in Toronto, Canada, aimed to analyze COVID-19 outcomes in 1975 SOTr across various SARS-CoV-2 waves and assess the impact of preventive and treatment measures. The primary outcome was severe COVID-19, defined as requiring supplemental oxygen, with secondary outcomes including hospitalization, length of stay, intensive care unit (ICU) admission, and 30-day and 1-year all-cause mortality. SARS-CoV-2 waves were categorized as Wildtype/Alpha/Delta (318 cases, 16.1%), Omicron BA.1 (268, 26.2%), Omicron BA.2 (268, 13.6%), Omicron BA.5 (561, 28.4%), Omicron BQ.1.1 (188, 9.5%), and Omicron XBB.1.5 (123, 6.2%). Severe COVID-19 rate was highest during the Wildtype/Alpha/Delta wave (44.6%), and lower in Omicron waves (5.7%-16.1%). Lung transplantation was associated with severe COVID-19 (OR: 4.62, 95% CI: 2.71-7.89), along with rituximab treatment (OR: 4.24, 95% CI: 1.04-17.3), long-term corticosteroid use (OR: 3.11, 95% CI: 1.46-6.62), older age (OR: 1.51, 95% CI: 1.30-1.76), chronic lung disease (OR: 2.11, 95% CI: 1.36-3.30), chronic kidney disease (OR: 2.18, 95% CI: 1.17-4.07), and diabetes (OR: 1.97, 95% CI: 1.37-2.83). Early treatment and ≥3 vaccine doses were associated with reduced severity (OR: 0.29, 95% CI: 0.19-0.46, and 0.35, 95% CI: 0.21-0.60, respectively). Tixagevimab/cilgavimab and bivalent boosters did not show a significant impact. The study concludes that COVID-19 severity decreased across different variants in SOTr. Lung transplantation was associated with worse outcomes and may benefit more from preventive and early therapeutic interventions.

Immunogenicity and clinical effectiveness of mRNA vaccine booster against SARS-CoV-2 Omicron in patients with haematological malignancies: A national prospective cohort study.

Information regarding the protective anti-SARS-CoV-2 antibody levels and the effectiveness of the mRNA vaccines against the Omicron variant in patients with haematological malignancies is limited. We prospectively followed two times BNT162b2 vaccinated oncohaematological patients (n = 1010) without prior COVID-19 for PCR-confirmed breakthrough infections during the Alpha/Delta and the Omicron phases of the pandemic. Anti-S1-IgG levels were longitudinally monitored in patients who had received the third (booster) vaccine dose. Patients with anti-S1-IgG levels <50 BAU/mL 1 month after the booster had a higher risk of Omicron infections (RR 1.91; 95% CI 1.39-2.63; p = 0.0001) and severe infections (RR 8.74; 95% CI 3.99-19.1; p < 0.0001). Conversely, the risk of severe COVID-19 was <1% with anti-S1-IgG levels >500 BAU/mL and neutralizing antibody concentrations >50 U/mL. The risks of breakthrough Omicron infections (HR 0.55; 95% CI 0.32-0.96; p = 0.034) and severe COVID-19 (HR 0.27; 95% 0.11-0.7; p = 0.0074) were lower among patients who had received the booster dose. In conclusion, low antibody levels are associated with significantly increased risk of both the breakthrough Omicron infections and severe COVID-19. The third mRNA vaccine dose improved the protection against the Omicron and reduced the risk of severe disease.

Immunogenicity and safety of RAZI recombinant spike protein vaccine (RCP) as a booster dose after priming with BBIBP-CorV: a parallel two groups, randomized, double blind trial.

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.