New England Journal of Medicine

BackgroundBooster doses of COVID-19 vaccines help restore protection against waning immunity and emerging variants. Having found that fractional BNT162b2 boosters were non-inferior to standard boosters in eliciting anti-spike IgG responses at day 28 in Mongolian adults, we assessed long-term immunogenicity and safety in the same cohort. MethodsIn this randomised, controlled, non-inferiority trial, adults previously vaccinated with two doses of ChAdOx1-S, BBIBP-CorV, or Gam-COVID-Vac were randomly assigned (1:1) to receive a 15g (fractional) or 30g (standard) BNT162b2 booster. IgG concentrations and functional surrogate virus neutralisation test (sVNT) levels against Wuhan-Hu-1 and Omicron BA.1 were assessed over 24 months. A subset had IFN-{gamma} cell-mediated-immunity (CMI) measured (Ag1/Ag2). Immune response GMRs (fractional:standard) were estimated from log-transformed values via multivariable linear regression. SARS-CoV-2 infections, adverse events, and serious adverse events (SAEs) were recorded. ClinicalTrials.gov Identifier: NCT05265065. FindingsOf 601 participants enrolled between May 27 and Sept 30, 2022, 520 (86.5%) completed 24-month follow-up. Although IgG levels declined from six to 24 months, relative responses remained similar between arms at 18 months (GMR 1{middle dot}08 [95% CI 0{middle dot}97-1{middle dot}22]) and 24 months (GMR 1{middle dot}06 [95% CI 0{middle dot}95-1{middle dot}18]). In the CMI subset, IFN-{gamma} responses peaked at day 28, waned to 18 months, and returned to baseline by 24 months, with fractional and standard arms similar at 24-month GMRs (Ag1 GMR 1{middle dot}17 [95% CI 0{middle dot}82-1{middle dot}66]; Ag2 GMR 1{middle dot}06 [95% CI 0{middle dot}73-1{middle dot}54]). Median sVNT inhibition against both Wuhan-Hu-1 and Omicron BA.1 was high and comparable between groups at 18 and 24 months (both 88% [95% CI 86-90]). SARS-CoV-2 infection was confirmed in 28 participants, with an additional 386 suspected infections after day 28, inferred from a >1{middle dot}2-fold rise in IgG titres between study visits. No SARS-Cov-2 infections resulted in hospitalisation. Fifty-three SAEs were reported, evenly distributed between groups, with no vaccine-related events. InterpretationFractional and standard BNT162b2 boosters showed comparable neutralising activity (sVNT) that persisted to 24 months, while binding IgG declined to baseline by 24 months. In the CMI subset, IFN-{gamma} responses followed a similar trajectory, indicating alignment of humoral and cellular immunity over time. Despite widespread SARS-CoV-2 circulation, no COVID-19 hospitalisations or deaths occurred, and safety was reassuring. These data support fractional dosing as a pragmatic, cost-saving option. FundingCoalition for Epidemic Preparedness Innovations (CEPI). This study was supported by the Victorian Governments Operational Infrastructure Support Programme. Panel: Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to Aug 27, 2025, for English-language studies in adults assessing immune responses to fractional or reduced-dose COVID-19 boosters, focusing on mRNA vaccines and long-term follow-up. Search terms combined "fractional dose", "low dose", "reduced dose", "booster", "immunogenicity", "antibodies", "durability", "persistence", and related terms. Evidence is limited and largely confined to short- and medium-term follow-up. A trial in Thailand found half-dose AZD1222 after CoronaVac was non-inferior to a full dose at 14 and 90 days, with lower reactogenicity.1 A subsequent Thai study showed half-dose BNT162b2 or AZD1222 after CoronaVac achieved non-inferior immunogenicity at 28 and 90 days, particularly with longer intervals.2 In the UK, COV-BOOST reported similar anti-spike IgG responses with half- and full-dose BNT162b2 at three months,3 and by eight months, decay patterns varied by platform, but half-dose BNT162b2 tracked closely with full doses.4 In Belgium, the IMCOVAS trial showed low-dose mRNA-1273 and heterologous schedules were non-inferior to reference regimens up to one year, though intradermal vaccination was less effective.5 In Brazil, the FRACT-COV trial followed 1451 adults for six months: full-dose BNT162b2 elicited the highest titres, but fractional BNT162b2 outperformed full-dose AZD1222 and Sinovac.6 Across studies, fractional mRNA boosters generally induced robust short-term responses and, in some cases, non-inferior durability up to 12 months. However, no trial had reported a 24-month follow-up of fractional versus standard intramuscular BNT162b2 boosters. Added value of this studyThis randomised trial is the first to provide 24-month data comparing fractional (15 {micro}g) and standard (30 {micro}g) BNT162b2 boosters in adults primed with non-mRNA vaccines (ChAdOx1-S, BBIBP-CorV, Gam-COVID-Vac). Fractional dosing produced humoral and cellular responses equivalent to standard dosing: anti-spike IgG declined to baseline by 24 months, but neutralising activity and IFN-{gamma} responses were preserved, with geometric mean ratios consistently close to unity. Age-stratified analyses showed higher early IgG responses in older adults that converged with younger participants by 18-24 months, indicating similar long-term durability across age groups. With 87% retention, detailed serological follow-up, and prespecified sensitivity analyses confirming that missingness did not bias results, this trial provides the first randomised long-term evidence from an LMIC setting. Our findings extend shorter-term results from Brazil, Thailand, and the UK by showing persistence of humoral and cellular immunity for two years. Implications of all the available evidenceFractional BNT162b2 boosters provide durable humoral and cellular immunity comparable to standard dosing, now shown up to 24 months. This supports dose-sparing as a feasible, cost-saving strategy to extend vaccine supply and improve equity, particularly in LMICs reliant on inactivated or adenoviral vector priming. While continued surveillance of emerging variants is needed, the available evidence indicates that fractional dosing can be used without compromising long-term protection.

BackgroundProtection against SARS-CoV-2 symptomatic infection and severe COVID-19 of previous infection, mRNA two-dose vaccination, mRNA three-dose vaccination, and hybrid immunity of previous infection and vaccination were investigated in Qatar for the Alpha, Beta, and Delta variants. MethodsSix national, matched, test-negative, case-control studies were conducted between January 18-December 18, 2021 on a sample of 239,120 PCR-positive tests and 6,103,365 PCR-negative tests. ResultsEffectiveness of previous infection against Alpha, Beta, and Delta reinfection was 89.5% (95% CI: 85.5-92.3%), 87.9% (95% CI: 85.4-89.9%), and 90.0% (95% CI: 86.7-92.5%), respectively. Effectiveness of two-dose BNT162b2 vaccination against Alpha, Beta, and Delta infection was 90.5% (95% CI, 83.9-94.4%), 80.5% (95% CI: 79.0-82.0%), and 58.1% (95% CI: 54.6-61.3%), respectively. Effectiveness of three-dose BNT162b2 vaccination against Delta infection was 91.7% (95% CI: 87.1-94.7%). Effectiveness of hybrid immunity of previous infection and two-dose BNT162b2 vaccination was 97.4% (95% CI: 95.4-98.5%) against Beta infection and 94.5% (95% CI: 92.8-95.8%) against Delta infection. Effectiveness of previous infection and three-dose BNT162b2 vaccination was 98.1% (95% CI: 85.7-99.7%) against Delta infection. All five forms of immunity had >90% protection against severe, critical, or fatal COVID-19 regardless of variant. Similar effectiveness estimates were observed for mRNA-1273. ConclusionsAll forms of natural and vaccine immunity prior to Omicron introduction provided strong protection against infection and severe COVID-19. Hybrid immunity conferred the strongest protection and its level was consistent with previous-infection immunity and vaccine immunity acting independently of each other.

PREVENT-19, the pivotal phase 3 trial of the Novavax adjuvanted, recombinant spike protein COVID-19 vaccine (NVX-CoV2373) demonstrated that the vaccine was safe and efficacious (vaccine efficacy, VE= 90%) for the prevention of symptomatic COVID-19. In the trial, participants were randomly assigned in a 2:1 ratio to receive 2 doses of NVX-CoV2373 or placebo 21 days apart. Throughout the study, SARS-CoV-2 circulating variant was predominantly alpha, but other variants circulated (i.e., beta, gamma, epsilon, and iota). VE among the per-protocol efficacy analysis population was calculated according to pre-specified disease severity (mild, moderate, or severe) criteria, but the impact on the risk of COVID-19- associated hospitalization was not specifically investigated. During the placebo-controlled portion of the trial (January 25, 2021, to April 30, 2021), 4 hospitalizations occurred among the 77 events analyzed for the primary endpoint using the per-protocol population, 0 among vaccine recipients and 4 among placebo recipients, yielding a VE against hospitalization of 100% (95% CI: 28.8, 100). Among an expanded efficacy population, which included COVID-19-associated hospitalizations without a requirement for diagnostic polymerase chain reaction testing performed at the study central laboratory, 12 total hospitalizations were identified, 0 among vaccine recipients and 12 among placebo recipients, yielding a post hoc VE against hospitalization of 100% (95% CI: 83.1, 100). These additional data from the PREVENT-19 trial provide relevant public health information concerning the attributes of NVX-CoV2373.

BACKGROUNDThis study has assessed a new Anti-COVID-19 Monoclonal Antibody Nasal Spray (SA58) for post-exposure prophylaxis (PEP) against symptomatic coronavirus disease 2019 (COVID-19). METHODSWe conducted an efficacy study in adults aged 18 years and older within three days of exposure to a SARS-CoV-2 infected individual. Recruited participants were randomized in a ratio of 3:1 to receive SA58 or placebo. Primary endpoints were laboratory-confirmed symptomatic COVID-19 within study period. FINDINGSA total of 1,222 participants were randomized and dosed (SA58, n=901; placebo, n=321). Median of follow-up was 2{middle dot}25 days and 2{middle dot}79 days for SA58 and placebo, respectively. Adverse events occurred in 221 of 901 (25%) and 72 of 321 (22%) participants with SA58 and placebo, respectively, with no significant difference (P=0{middle dot}49). All adverse events were mild in severity. Laboratory-confirmed symptomatic COVID-19 developed in 7 of 824 participants (0{middle dot}22 per 100 person-days) in the SA58 group vs 14 of 299 (1{middle dot}17 per 100 person-days) in the placebo group, resulting in an estimated efficacy of 80 {middle dot} 82% (95%CI 52 {middle dot} 41%-92 {middle dot} 27%). There were 32 SARS-CoV-2 RT-PCR positives (1{middle dot}04 per 100 person-days) in the SA58 group vs 32 (2{middle dot}80 per 100 person-days) in the placebo group, resulting in an estimated efficacy of 61{middle dot}83% (95%CI 37{middle dot} 50%-76{middle dot} 69%). A total of 21 RT-PCR positive samples were sequenced. 21 lineages of SARS-CoV-2 variants were identified, and all were the Omicron variant BF{middle dot}7. INTERPRETATIONSA58 Nasal Spray showed favorable efficacy and safety in preventing SARS-CoV-2 infection or symptomatic COVID-19 in healthy adult workers who had exposure to SARS-CoV-2 within 72 hours. FUNDINGNo funding was received for this study. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSMonoclonal antibodies (mAbs) and the post-exposure prophylaxis (PEP) with mAbs represent a very important public health strategy against COVID-19 outbreak. SA58 Nasal Spray is a broad-spectrum anti-COVID-19 mAb, developed by Sinovac Life Sciences Ltd. for treatment and prophylaxis against COVID-19. SA58 has been shown to potently neutralize ACE2-utilizing sarbecoviruses, including most of circulating Omicron variants. We searched PubMed on Nov 21, 2022, for published clinical trials, with no language or date restrictions, using various combinations of the search terms of "monoclonal antibodies", "SARS-CoV-2", "COVID-19", "prophylaxis", and "prevention". Three published trials were identified. The first study reported the efficacy of AZD7442 (tixagevimab/cilgavimab) PEP against symptomatic COVID-19 in adults aged [≥]18 years over a 183-day follow-up period. The primary efficacy end point of post-exposure prevention of symptomatic COVID-19 was not met, though AZD7442 showed promising results in participants who were SARS-CoV-2 RT-PCR negative at baseline. The second study reported the efficacy and safety of bamlanivimab for COVID-19 prevention in household contacts of individuals with a SARS-CoV-2 infection in a high-risk transmission setting over a one-month efficacy assessment period. The third study reported REGEN-COV (casirivimab/imdevimab) for preventing symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Both bamlanivimab and REGEN-COV showed satisfactory safety profile and efficacy against COVID-19 and were licensed for PEP use in the U.S. However, due to the circulating Omicron variants have developed significant escape properties, the emergency use authorization of bamlanivimab and REGEN-COV for treatment and PEP against COVID-19 has been discontinued by the U.S. Food and Drug Administration. Till the end of December 2022, no drug was available for PEP use against COVID-19. Added value of this studyDuring a recent large outbreak of the Omicron BF{middle dot}7 sublineage in Beijing, our preliminary results in healthy adults within 72 hours of contact with SARS-CoV-2-infected individuals showed that SA58 nasal spray was highly effective in preventing symptomatic COVID-19 and SARS-CoV-2 infection caused by the sublineage, which variants have shown significant escape of immunity in previous studies. SA58 was able to significantly lower the risk of laboratory-confirmed COVID-19 by 80{middle dot}82% (95%CI 52{middle dot}41%-92{middle dot}27%) and of SARS-CoV-2 infection by 61{middle dot}83% (95%CI 37{middle dot}50%-76{middle dot}69%) in our study participants. Implications of all the available evidenceThis trial showed the ability of a nasal spray of broad-spectrum anti-COVID-19 mAb SA58 to provide satisfactory protection against one circulating Omicron strain of SARS-CoV-2. The drug had a favorable safety profile and was well tolerated by healthy adults. This newly developed mAb is resistant to SARS-CoV-2 mutations and may provide a new powerful countermeasure to tackle against the immunity-escaping variants of SARS-CoV-2 circulating in the population. The intranasal administration of SA58 is novel and has many advantages over intramuscular injections of mAbs previously licensed, as it is less invasive and more acceptable in recipients. Auto-administration with easiness of use may allow early administration, probably a key feature for prevention.

BackgroundTixagevimab and cilgavimab (AZD7442) are two monoclonal antibodies developed by AstraZeneca for the pre-exposure prophylaxis and treatment of patients infected by SARS-CoV-2. Its effectiveness and safety in patients hospitalized with COVID-19 was not known at the outset of this trial. MethodsDisCoVeRy is a phase 3, adaptive, multicentre, randomized, controlled trial conducted in 63 sites in Europe. Participants were randomly assigned (1:1) to receive placebo or tixagevimab-cilgavimab in addition to standard of care. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale. Several clinical, virological, immunological and safety endpoints were also assessed. FindingsDue to slow enrolment, recruitment was stopped on July 1st, 2022. The antigen positive modified intention-to-treat population (mITT) was composed of 173 participants randomized to tixagevimab-cilgavimab (N = 91) or placebo (N = 82), 91.9% (159/173) with supplementary oxygen, and 47.4% (82/173) previously vaccinated at inclusion. There was no significant difference in the distribution of the WHO ordinal scale at day 15 between the two groups (odds ratio (OR) 0.93, 95%CI [0.54-1.61]; p = 0.81) nor in any clinical, virological or safety secondary endpoints. In the global mITT (N = 226), neutralization antibody titers were significantly higher in the tixagevimab-cilgavimab group/patients compared to placebo at day 3 (Least-squares mean differences (LSMD) 1.44, 95% Confidence interval (CI) [1.20-1.68]; p < 10-23) and day 8 (LSMD 0.91, 95%CI [0.64-1.18]; p < 10-8) and it was most important for patients infected with a pre-omicron variant, both at day 3 (LSMD 1.94, 95% CI [1.67-2.20], p < 10-25) and day 8 (LSMD 1.17, 95% CI [0.87-1.47], p < 10-9), with a significant interaction (p < 10-7 and p = 0.01 at days 3 and 8, respectively). InterpretationThere were no significant differences between tixagevimab-cilgavimab and placebo in clinical endpoints, however the trial lacked power compared to prespecified calculations. Tixagevimab-cilgavimab was well tolerated, with low rates of treatment related events. FundingTrial registration: ClinicalTrials.gov NCT04315948. Registered on 13 March 2020 updated on 22 April 2021.

ObjectivesWe report interim safety and immunogenicity results from a phase 3 study of omicron-BA.1 variant-containing (mRNA-1273.214) primary vaccination series (Part 1) and booster dose (Part 2) in children aged 6 months to 5 years (NCT05436834). MethodsIn Part 1, SARS-CoV-2 unvaccinated participants, including participants who received placebo in the KidCOVE study (NCT04796896), received 2 doses of mRNA-1273.214 (25-g omicron-BA.1 and ancestral Wuhan-Hu-1 mRNA 1:1 co-formulation) primary series. In Part 2, participants who previously completed the mRNA-1273 (25-{micro}g) primary series in KidCOVE received a mRNA-1273.214 (10-g) booster dose. Primary objectives were safety, reactogenicity, and immunogenicity, including prespecified immune response success criteria. ResultsAt the data cutoff (December 5, 2022), 179 participants had received [&ge;]1 dose of mRNA-1273.214 primary series (Part 1) and 539 participants had received a mRNA-1273.214 booster dose (Part 2). The safety profile of mRNA-1273.214 primary series and booster dose was consistent with that of the mRNA-1273 primary series in this same age group, with no new safety concerns identified and no vaccine-related serious adverse events observed. Compared with neutralizing antibody responses induced by the mRNA-1273 primary series, both the mRNA-1273.214 primary series and booster elicited responses that were superior against omicron-BA.1 and non-inferior against ancestral Wuhan-Hu-1(D614G). ConclusionsmRNA-1273.214 was immunogenic against BA.1 and D614G in children aged 6 months to 5 years, with a comparable safety profile to mRNA-1273, when given as a 2-dose primary series or as a booster dose after the mRNA-1273 primary series. Clinical Trial RegistryNCT05436834

BackgroundThe safety and immunogenicity of heterologous prime-boost COVID-19 vaccine regimens with one shot of a recombinant adenovirus type-5-vectored COVID-19 vaccine Convidecia has not been reported. MethodsWe conducted a randomized, controlled, observer-blinded trial of heterologous prime-boost immunization with CoronaVac and Convidecia in healthy adults 18-59 years of age. Eligible participants who were primed with one or two doses of CoronaVac were randomly assigned at a 1:1 ratio to receive a booster dose of Convidecia or CoronaVac. Participants were masked to the vaccine received but not to the three-dose or two-dose regimen. The occurrences of adverse reactions within 28 days after the vaccination were documented. The geometric mean titers of neutralizing antibodies against live SARS-CoV-2 virus were measured at 14 and 28 days after the booster vaccination. ResultsBetween May 25 and 26, 2021, a total of 300 participants were enrolled. Participants who received a booster shot with a heterologous dose of Convidecia reported increased frequencies of solicited injection-site reactions than did those received a homogeneous dose of CoronaVac, but frequencies of systemic reactions. The adverse reactions were generally mild to moderate. The heterologous immunization with Convidecia induced higher live viral neutralizing antibodies than did the homogeneous immunization with CoronaVac (197.4[167.7, 232.4] vs. 33.6[28.3, 39.8] and 54.4[37. 9, 78.0] vs. 12.8[9.3, 17.5]) at day 14 in the three- and two-dose regimen cohort, respectively. ConclusionsThe heterologous prime-boost regimen with Convidecia after the priming with CoronaVac was safe and significantly immunogenic than a homogeneous boost with CoronaVac (ClinicalTrials.gov, number NCT04892459).

BackgroundExisting parenteral SARS-CoV-2 vaccines protect against severe disease but do not reliably prevent infection or reinfection. Inhaled vaccines may elicit localized immunity in the respiratory tract, a principal entry site for SARS-CoV-2. MethodsIn this investigator-initiated, single-center, open-label phase 1 trial (NCT05226390, ClinicalTrials.gov), 23 healthy adults previously immunized with EU-approved SARS-CoV-2 vaccines received a single inhaled dose of Modified Vaccinia virus Ankara-(MVA)-SARS-2-ST (1x107 IU), engineered to express a prefusion-stabilized SARS-CoV-2 spike. Participants were followed for 140 days. Primary endpoints included solicited local and systemic reactogenicity through day 7, unsolicited adverse events through day 28, serious adverse events throughout, and changes in spirometry and laboratory parameters. Secondary endpoints were changes in SARS-CoV-2 S1-specific IgG in serum and bronchoalveolar lavage; exploratory endpoints included changes in S1-specific IgA in serum and bronchoalveolar lavage, and methacholine responsiveness. ResultsNo serious adverse events were observed. Over 28 days, mild or moderate adverse events occurred in 87% of participants, predominantly cough, headache, and fatigue, all resolved. Pulmonary function and methacholine responsiveness were stable, except for one transient 20% decrease in FEV1 on Day 14 that normalized subsequently. Serum IgG responses remained minimal, whereas a subset displayed increased bronchoalveolar IgA. ConclusionA single inhaled booster dose of MVA-SARS-2-ST was safe and generally well tolerated. While systemic antibody levels did not rise substantially, the observed mucosal IgA response in some participants points to a localized mucosal effect. Further studies are warranted to clarify underlying mechanisms and the significance of this response in diverse populations.

In vivo CRISPR gene therapy holds large clinical potential, but the safety and efficacy remain largely unknown. Here, we injected a single dose of HSV-1-targeting CRISPR formulation in the cornea of three patients with severe refractory herpes stromal keratitis (HSK) during corneal transplantation. Our study is an investigated initiated, open-label, single-arm, non-randomized interventional trial at a single center (NCT04560790). We found neither detectable CRISPR-induced off-target cleavages by GUIDE-seq nor systemic adverse events for 18 months on average in all three patients. The HSV-1 remained undetectable during the study. Our preliminary clinical results suggest that in vivo gene editing targeting the HSV-1 genome holds acceptable safety as a potential therapy for HSK. One-Sentence SummaryOur study is the first in vivo CRISPR therapy for treating infectious disease and the first virus-like particle (VLP)-delivered gene therapy, reporting clinical follow-up to 21 months in HSK patients without seeing virus relapse, HSK recurrence, and CRISPR-associated side effects.

BACKGROUNDOver 20% of cases and 0.4% of deaths from Covid-19 occur in children. Following demonstration of safety and efficacy of the adjuvanted, recombinant spike protein vaccine NVX-CoV2373 in adults, the PREVENT-19 trial enrolled adolescents. METHODSSafety, immunogenicity, and efficacy of NVX-CoV2373 were evaluated in adolescents aged 12 to <18 years in an expansion of PREVENT-19, a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States. Participants were randomized 2:1 to two doses of NVX-CoV2373 or placebo 21 days apart, and followed for a median of 2 months after second vaccination. Primary end points were serologic non-inferiority of neutralizing antibody (NA) responses compared with young adults (18 to <26 years) in PREVENT-19, protective efficacy against laboratory-confirmed Covid-19, and assessment of reactogenicity/safety. RESULTSAmong 2,247 participants randomized between April-June 2021, 1,491 were allocated to NVX-CoV2373 and 756 to placebo. Post-vaccination, the ratio of NA geometric mean titers in adolescents compared to young adults was 1.5 (95% confidence interval [CI] 1.3 to 1.7). Twenty Covid-19 cases (all mild) occurred: 6 among NVX-CoV2373 and 14 among placebo recipients (vaccine efficacy [VE]: 79.5%, 95% CI, 46.8 to 92.1). All sequenced viral genomes (11/20) were identified as Delta variant (Delta variant VE: 82.0% [95% CI: 32.4 to 95.2]). Reactogenicity was largely mild-to-moderate, transient, and more frequent in NVX-CoV2373 recipients and after the second dose. Serious adverse events were rare and evenly distributed between treatments. CONCLUSIONSNVX-CoV2373 was safe, immunogenic, and efficacious in the prevention of Covid-19 and those cases caused by the Delta variant in adolescents. (Funded by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; PREVENT-19 ClinicalTrials.gov number, NCT04611802).

BackgroundWe report the clinical efficacy against COVID-19 infection of BBV152, a whole-virion inactivated SARS-CoV-2 vaccine formulated with a Toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG). MethodsWe did a double-blind, randomised, multicentre, phase 3 clinical trial in 25 Indian hospitals to evaluate the efficacy, safety, and immunological lot consistency of BBV152. Healthy adults (age 18-98 years) randomised 1:1 using a computer-generated randomisation scheme received two intramuscular doses of vaccine or placebo administered four weeks apart. The primary outcome was laboratory-confirmed symptomatic COVID-19, occurring at least 14 days after the second dose. Secondary outcomes were efficacy in sub-groups for age (18-< 60 years and [&ge;] 60 years) and in participants with pre-existing stable medical conditions. We also evaluated safety, reactogenicity, and consistency of immune responses for three consecutive manufacturing lots. FindingsBetween November 16, 2020 and January 7, 2021 we recruited 25,798 participants who were randomised to BBV152 or placebo groups; 24,419 received two doses of BBV152 (n = 12,221) or placebo (n = 12,198). In a case-driven analysis, 130 cases of symptomatic COVID-19 were reported in 16,973 (0{middle dot}77%) participants with follow-up at least two weeks after the second vaccination; 24 occurred in the vaccine group and 106 in placebo recipients giving an overall vaccine efficacy of 77{middle dot}8% (95% CI: 65{middle dot}2-86{middle dot}4). Sixteen cases, one vaccinee and 15 placebo recipients, met the severe symptomatic COVID-19 case definition giving a vaccine efficacy of 93{middle dot}4% (57{middle dot}1-99{middle dot}8). Efficacy against asymptomatic COVID-19 was 63{middle dot}6% (29{middle dot}0-82{middle dot}4). BBV152 conferred 65{middle dot}2% (95% CI: 33{middle dot}1-83{middle dot}0) protection against the SARS-CoV-2 Variant of Concern, B.1.617.2 (Delta). BBV152 was well tolerated with no clinically or statistically significant differences in the distributions of solicited, unsolicited, or serious adverse events between vaccine and placebo groups. No cases of anaphylaxis or vaccine-related deaths were reported. InterpretationBBV152 was immunogenic and highly efficacious against symptomatic and asymptomatic COVID-19 variant associated disease, particularly against severe disease in adults. Vaccination was well tolerated with an overall incidence of adverse events observed over a median of 146 days that was lower than that observed with other COVID-19 vaccines. FundingThis work was supported and funded by Bharat Biotech International Limited and partly co-funded by the Indian Council of Medical Research. Clinicaltrials.gov: NCT04641481

BackgroundCOVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. MethodsWe conducted a global Phase 3, multi-stage efficacy study (NCT04904549) among adults aged [&ge;]18 years. Participants were randomized 1:1 to receive two intramuscular injections 21 days apart of a bivalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (5 g of ancestral (D614) and 5 g of B.1.351 [beta] variant spike protein) or placebo. Symptomatic COVID-19 was defined as laboratory-confirmed COVID-19 with COVID-19-like illness (CLI) symptoms. The primary efficacy endpoint was the prevention of symptomatic COVID-19 [&ge;]14 days after the second injection (post-dose 2 [PD2]). ResultsBetween 19 Oct 2021 and 15 Feb 2022, 12,924 participants received [&ge;]1 study injection. 75% of participants were SARS-CoV-2 non-naive. 11,416 participants received both study injections (efficacy-evaluable population [vaccine, n=5,736; placebo, n=5,680]). Up to 15 March 2022, 121 symptomatic COVID-19 cases were reported (32 in the vaccine group and 89 in the placebo group) [&ge;]14 days PD2 with a vaccine efficacy (VE) of 64.7% (95% confidence interval [CI] 46.6; 77.2%). VE was 75.1% (95% CI 56.3; 86.6%) in non-naive and 30.9% (95% CI -39.3; 66.7%) in naive participants. Viral genome sequencing identified the infecting strain in 68 cases (Omicron [BA.1 and BA.2 subvariants]: 63; Delta: 4; Omicron and Delta: 1). The vaccine was well-tolerated and had an acceptable safety profile. ConclusionsA bivalent vaccine conferred heterologous protection against symptomatic infection with newly emergent Omicron (BA.1 and BA.2) in non-naive adults 18-59 years of age. ClinicalTrials.govNCT04904549

The B.1.1.529 (Omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in November of 2021 in South Africa and Botswana as well as in a sample of a traveler from South Africa in Hong Kong.1,2 Since then, B.1.1.529 has been detected in many countries globally. This variant seems to be more infectious than B.1.617.2 (Delta), has already caused super spreader events3 and has outcompeted Delta within weeks in several countries and metropolitan areas. B.1.1.529 hosts an unprecedented number of mutations in its spike gene and early reports have provided evidence for extensive immune escape and reduced vaccine effectiveness.2,4-6 Here, we investigated the neutralizing and binding activity of sera from convalescent, mRNA double vaccinated, mRNA boosted as well as convalescent double vaccinated and convalescent boosted individuals against wild type, B.1.351 and B.1.1.529 SARS-CoV-2 isolates. Neutralizing activity of sera from convalescent and double vaccinated participants was undetectable to very low against B.1.1.529 while neutralizing activity of sera from individuals who had been exposed to spike three or four times was maintained, albeit at strongly reduced levels. Binding to the B.1.1.529 receptor binding domain (RBD) and N-terminal domain (NTD) was reduced in convalescent not vaccinated but was mostly retained in vaccinated individuals.

BackgroundInformation on the safety and immunogenicity of the omicron BA.4/BA.5-containing bivalent booster mRNA-1273.222 are needed. MethodsIn this ongoing, phase 2/3 trial, 50-g mRNA-1273.222 (25-g each ancestral Wuhan-Hu-1 and omicron BA.4/BA.5 spike mRNAs) is compared to 50-g mRNA-1273, administered as second boosters in adults who previously received a 2-injection (100-g) primary series and first booster (50-g) dose of mRNA-1273. The primary objectives were safety and immunogenicity 28 days post-boost. ResultsParticipants received 50-g of mRNA-1273 (n=376) or mRNA-1273.222 (n=511) as second booster doses. Omicron BA.4/BA.5 and ancestral SARS-CoV-2 D614G neutralizing antibody geometric mean titers (GMTs [95% confidence interval]) after mRNA-1273.222 (2324.6 [1921.2-2812.7] and 7322.4 [6386.2-8395.7]) were significantly higher than mRNA-1273 (488.5 [427.4-558.4] and 5651.4 (5055.7-6317.3) respectively, at day 29 post-boost in participants with no prior SARS-CoV-2-infection. A randomly selected subgroup (N=60) of participants in the mRNA-1273.222 group also exhibited cross-neutralization against the emerging omicron variants BQ.1.1 and XBB.1. No new safety concerns were identified with mRNA-1273.222. Vaccine effectiveness was not assessed in this study; in an exploratory analysis 1.6% (8/511) of mRNA-1273.222 recipients had Covid-19 post-boost. ConclusionThe bivalent omicron BA.4/BA.5-containing vaccine mRNA-1273.222 elicited superior neutralizing antibody responses against BA.4/BA.5 compared to mRNA-1273, with no safety concerns identified. (Supported by Moderna; ClinicalTrials.gov Identifier: NCT04927065)

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (Omicron) variant has led to growing concerns of increased transmissibility and escape of both natural and vaccine-induced immunity. In this analysis, sera from adult participants in a phase 2 clinical study (NCT04405076) were tested for neutralizing activity against B.1.1.529 after a 2-dose (100 {micro}g) mRNA-1273 primary vaccination series and after a 50-{micro}g mRNA-1273 booster dose. Results from this preliminary analysis show that 1 month after completing the primary series, mRNA-1273-elicited serum neutralization of B.1.1.529 was below the lower limit of quantification; however, neutralization was observed at 2 weeks after the mRNA-1273 booster dose, although at a reduced level relative to wild-type SARS-CoV-2 (D614G) and lower than that observed against D614G at 1 month after the primary series.

The early widespread dissemination of Omicron indicates the urgent need to better understand the transmission dynamics of this variant, including asymptomatic spread among immunocompetent and immunosuppressed populations. In early December 2021, the Ubuntu clinical trial, designed to evaluate efficacy of the mRNA-1273 vaccine (Moderna) among persons living with HIV (PLWH), began enrolling participants. Nasal swabs are routinely obtained at the initial vaccination visit, which requires participants to be clinically well to receive their initial jab. Of the initial 230 participants enrolled between December 2 and December 17, 2021, 71 (31%) were PCR positive for SARS-CoV-2: all of whom were subsequently confirmed by S gene dropout to be Omicron; 48% of the tested samples had cycle threshold (CT) values <25 and 18% less than 20, indicative of high titers of asymptomatic shedding. Asymptomatic carriage rates were similar in SARS-CoV-2 seropositive and seronegative persons (27% respectively). These data are in stark contrast to COVID-19 vaccine studies conducted pre-Omicron, where the SARS-CoV-2 PCR positivity rate at the first vaccination visit ranged from <1%-2.4%, including a cohort of over 1,200 PLWH largely enrolled in South Africa during the Beta outbreak. We also evaluated asymptomatic carriage in a sub study of the Sisonke vaccine trial conducted in South African health care workers, which indicated 2.6% asymptomatic carriage during the Beta and Delta outbreaks and subsequently rose to 16% in both PLWH and PHLWH during the Omicron period. These findings strongly suggest that Omicron has a much higher rate of asymptomatic carriage than other VOC and this high prevalence of asymptomatic infection is likely a major factor in the widespread, rapid dissemination of the variant globally, even among populations with high prior rates of SARS-COV-2 infection.

BackgroundProtection from SARS-CoV-2 vaccines wanes over time and is compounded by emerging variants including Omicron subvariants. This study evaluated safety and immunogenicity of SARS-CoV-2 variant vaccines. MethodsThis phase 2 open-label, randomized trial enrolled healthy adults previously vaccinated with a SARS-CoV-2 primary series and a single boost. Eligible participants were randomized to one of six Moderna COVID19 mRNA vaccine arms (50{micro}g dose): Prototype (mRNA-1273), Omicron BA.1+Beta (1 or 2 doses), Omicron BA.1+Delta, Omicron BA.1 monovalent, and Omicron BA.1+Prototype. Neutralization antibody titers (ID50) were assessed for D614G, Delta, Beta and Omicron BA.1 variants and Omicron BA.2.12.1 and BA.4/BA.5 subvariants 15 days after vaccination. ResultsFrom March 30 to May 6, 2022, 597 participants were randomized and vaccinated. Median age was 53 years, and 20% had a prior SARS-CoV-2 infection. All vaccines were safe and well-tolerated. Day 15 geometric mean titers (GMT) against D614G were similar across arms and ages, and higher with prior infection. For uninfected participants, Day 15 Omicron BA.1 GMTs were similar across Omicron-containing vaccine arms (3724-4561) and higher than Prototype (1,997 [95%CI:1,482-2,692]). The Omicron BA.1 monovalent and Omicron BA.1+Prototype vaccines induced a geometric mean ratio (GMR) to Prototype for Omicron BA.1 of 2.03 (97.5%CI:1.37-3.00) and 1.56 (97.5%CI:1.06-2.31), respectively. A subset of samples from uninfected participants in four arms were also tested in a different laboratory at Day 15 for neutralizing antibody titers to D614G and Omicron subvariants BA.1, BA.2.12.2 and BA.4/BA.5. Omicron BA.4/BA.5 GMTs were approximately one third BA.1 GMTs (Prototype 517 [95%CI:324-826] vs. 1503 [95%CI:949-2381]; Omicron BA.1+Beta 628 [95%CI:367-1,074] vs. 2125 [95%CI:1139-3965]; Omicron BA.1+Delta 765 [95%CI:443-1,322] vs. 2242 [95%CI:1218-4128] and Omicron BA.1+Prototype 635 [95%CI:447-903] vs. 1972 [95%CI:1337-2907). ConclusionsHigher Omicron BA.1 titers were observed with Omicron-containing vaccines compared to Prototype vaccine and titers against Omicron BA.4/BA.5 were lower than against BA.1 for all candidate vaccines. Clinicaltrials.govNCT05289037

BackgroundWe assessed the safety, tolerability and immunogenicity of VLA2001 is a whole-virion inactivated SARS-CoV-2 vaccine adsorbed to alum with a toll-like receptor 9 agonist adjuvant in healthy volunteers aged 18-55. MethodsThe first 15 participants were enrolled, in groups of 5, to receive two doses, separated by 21 days, of one of three dose concentrations, administered intramuscularly. 138 further participants were randomised 1:1:1 to receive the same 3 dose concentrations, in a double blinded manner. Primary outcomes were solicited adverse reactions 7 days after each vaccination and neutralising antibody geometric mean titres (GMT) against SARS-CoV-2, 2 weeks after the second vaccination (day 36), measured by live microneutralisation assay against wild-type virus (MNA50). Secondary outcomes included unsolicited adverse events, and humoral and cellular responses at day 36, measured by IgG ELISA against Spike protein and interferon-{gamma} secreting T-cells by ELISpot stimulated with multiple SARS-CoV-2 antigens. (ClinicalTrials.gov NCT04671017, ISRCTN 82411169) FindingsBetween December 16, 2020 and January 21, 2021, 153 participants were enrolled and randomised evenly between the dose groups. The rates of solicited reactions were similar after the first and second doses and between the three dose groups. The most frequent local reactions were tenderness (58{middle dot}2%) and pain (41{middle dot}8%) and systemic reactions were headache (46%) and fatigue (39{middle dot}2%). In the high dose group, two weeks following the second dose, the geometric mean titres were 530.4 (95% CI: 421{middle dot}49, 667{middle dot}52) for neutralizing antibodies and 2147{middle dot}9 (95% CI: 1705{middle dot}98, 2704{middle dot}22) for S-binding antibodies. There was a dose dependent response with 90{middle dot}0% (95% CI:78{middle dot}0%.,97{middle dot}0%) seroconversion (4-fold rise) at day 36 in the high dose group, which was significantly higher than rates in both the medium (73.5%; 95% CI: 59%,85%), CIs) and low dose (51%; 95%CI: 37%,65%) rate, CIs) groups (both p < 0.001). Antigen-specific interferon-{gamma} T-cells reactive against the S, M and N proteins were observed in 76, 36 and 49% of high dose recipients, respectively. InterpretationVLA2001-201 was well tolerated and produced both humoral and cellular immune responses, with a clear dose-response effect. FundingThis study was funded by the Department of Health and Social Care, UK The funder had no role in the study design, implementation or analysis.

BackgroundBooster vaccination is important because of waning immunity and variant immune evasion. We conducted a single-blinded, randomized trial to evaluate the safety, reactogenicity, and immunogenicity of heterologous booster vaccination in health care workers (HCW) who had received two doses of ChAdOx1 nCov-19. Methods and findingsHCW at least 90 days after the second dose were enrolled to receive one of the four vaccines: BNT162b2, half-dose mRNA-1273, mRNA-1273, and MVC-COV1901. The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. 340 HCW were enrolled: 83 received BNT162b2 (2 excluded), 85 half-dose mRNA-1273, 85 mRNA-1273, and 85 MVC-COV1901. mRNA vaccines had more reactogenicity than protein vaccine. Anti-spike IgG increased by a fold of 8.4 for MCV-COV1901, 32.2 for BNT162b2, 47.6 for half-dose mRNA-1273 and 63.2 for mRNA1273. The live virus microneutralization assay (LVMNA) against the wild type, alpha and delta variants were consistent with anti-spike IgG for all booster vaccines. The LVMNA in the four groups against omicron variant were 6.4 to 13.5 times lower than those against the wild type. Serum neutralizing antibody against omicron variant was undetectable in 60% of the participants who received MCV-COV1901 as a booster by LVMNA. By using pseudovirus neutralizing assay, we found that neutralization activity in the four groups against omicron variant were 4.6 to 5.2 times lower than that against the D614G. All booster vaccines induced comparable T cell response. ConclusionsThird dose booster not only increases neutralizing antibody titer but also enhances antibody capacity against SARS-CoV-2 variants. mRNA vaccines are preferred booster vaccines for those after primary series of ChAdOx1 nCov-19. Trial registrationClinicalTrials.gov NCT05132855

In this South African phase 1/2b study, we demonstrated vaccine efficacy (VE) of two doses of AZD1222 for asymptomatic and symptomatic SARS-CoV-2 infection: 90.6% against wild-type and 77.1% against the Delta variant [&ge;]9 months after vaccination. VE against infection with the Beta variant, which preceded circulation of Delta, was 6.7%. Clinical trial identifierCT.gov NCT04444674