New England Journal of Medicine

BackgroundIsraeli has vaccinated over 80% of its adult population, with two doses of the Pfizer BNT162b2 vaccine. This intervention has been highly successful in curtailing the coronavirus 2 outbreak. One major concern is the ability of the virus to mutate which potentially can cause SARS-CoV-2 to partially escape from the immune system. Here we evaluate the efficacy of the Pfizer vaccine against the B.1.351 variant. MethodsThe Ministry of Health, initiated sequencing of selected positive swab samples identified as being of interest. We used logistic regression, with variant type as the dependent variable, vaccination status as the main explanatory variable, controlling for age, sex, subpopulation, place of residence and time of sample, to estimate the odds ratio for a vaccinated case to have the B. 1.351 versus the B.1.1.7 variant, within vaccinated and unvaccinated persons who tested positive. FindingsThere were 19 cases of B.1.351 variant (3.2%) among those vaccinated more than 14 days before the positive sample and 88 (3.5%) among the unvaccinated. The estimated odds ratio was 1.29 [95% CI: 0.66-2.50]. From this result, assuming the efficacy against the B.1.1.7 variant to be 95%, the estimated efficacy against the B.1.351 variant was 94% [95% CI: 87-97%]. InterpretationDespite the concerns caused by the B.1.351 variant, the BNT162b2 vaccine seems to provide substantial immunity against both that variant and the B.1.1.7. Our results suggest that from 14 days following the second vaccine dose the efficacy of BNT162b2 vaccine is at most marginally affected by the B.1.351 variant. FundingNo funding

This study investigated the effectiveness of natural infection in preventing reinfection with the JN.1 variant during a large JN.1 wave in Qatar, using a test-negative case-control study design. The overall effectiveness of previous infection in preventing reinfection with JN.1 was estimated at only 1.8% (95% CI: -9.3-12.6%). This effectiveness demonstrated a rapid decline over time since the previous infection, decreasing from 82.4% (95% CI: 40.9-94.7%) within 3 to less than 6 months after the previous infection to 50.9% (95% CI: -11.8-78.7%) in the subsequent 3 months, and further dropping to 18.3% (95% CI: -34.6-56.3%) in the subsequent 3 months. Ultimately, it reached a negligible level after one year. The findings show that the protection of natural infection against reinfection with JN.1 is strong only among those who were infected within the last 6 months, with variants such as XBB*. However, this protection wanes rapidly and is entirely lost one year after the previous infection. The findings support considerable immune evasion by JN.1.

The BA.2.75* sublineage of SARS-CoV-2 B.1.1.529 (omicron) variant escapes neutralizing antibodies. We estimated effectiveness of prior infection in preventing reinfection with BA.2.75* using a test-negative, case-control study design. Effectiveness of prior pre-omicron infection against BA.2.75* reinfection, irrespective of symptoms, was 6.0% (95% CI: 1.5-10.4%). Effectiveness of prior BA.1/BA.2 infection was 49.9% (95% CI: 47.6-52.1%) and of prior BA.4/BA.5 infection was 80.6% (95% CI: 71.2-87.0). Effectiveness of prior pre-omicron infection followed by BA.1/BA.2 infection against BA.2.75* reinfection was 56.4% (95% CI: 50.5-61.6). Effectiveness of prior pre-omicron infection followed by BA.4/BA.5 infection was 91.6% (95% CI: 65.1-98.0). Analyses stratified by time since prior infection indicated waning of protection since prior infection. Analyses stratified by vaccination status indicated that protection from prior infection is higher among those vaccinated, particularly among those ...

Laboratory science evidence suggests possibility of immune imprinting, a negative impact for vaccination on subsequent protective immunity against SARS-CoV-2 infection. We investigated differences in incidence of SARS-CoV-2 reinfection in the cohort of persons who had a primary omicron infection, but different vaccination histories using matched, national, retrospective, cohort studies. Adjusted hazard ratio (AHR) for incidence of reinfection, factoring also adjustment for differences in testing rate, was 0.43 (95% CI: 0.39-0.49) comparing history of two-dose vaccination to no vaccination, 1.47 (95% CI: 1.23-1.76) comparing history of three-dose vaccination to two-dose vaccination, and 0.57 (95% CI: 0.48-0.68) comparing history of three-dose vaccination to no vaccination. Divergence in cumulative incidence curves increased markedly when incidence was dominated by BA.4/BA.5 and BA.2.75* omicron subvariant. History of primary-series vaccination enhanced immune protection against omicron reinfection, but history of booster vaccination compromised protection against omicron reinfection. These findings do not undermine the short-term public health utility of booster vaccination. TeaserHistory of booster vaccination showed lower protection against omicron reinfection than history of two-dose vaccination.

BackgroundLong-term effectiveness of COVID-19 mRNA boosters in populations with different prior infection histories and clinical vulnerability profiles is inadequately understood. MethodsA national, matched, retrospective, target trial cohort study was conducted in Qatar to investigate effectiveness of a third mRNA (booster) dose, relative to a primary series of two doses, against SARS-CoV-2 omicron infection and against severe COVID-19. Associations were estimated using Cox proportional-hazards regression models. ResultsBooster effectiveness relative to primary series was 41.1% (95% CI: 40.0-42.1%) against infection and 80.5% (95% CI: 55.7-91.4%) against severe, critical, or fatal COVID-19, over one-year follow-up after the booster. Among persons clinically vulnerable to severe COVID-19, effectiveness was 49.7% (95% CI: 47.8-51.6%) against infection and 84.2% (95% CI: 58.8-93.9%) against severe, critical, or fatal COVID-19. Effectiveness against infection was highest at 57.1% (95% CI: 55.9-58.3%) in the first month after the booster but waned thereafter and was modest at only 14.4% (95% CI: 7.3-20.9%) by the sixth month. In the seventh month and thereafter, coincident with BA.4/BA.5 and BA.2.75* subvariant incidence, effectiveness was progressively negative reaching -20.3% (95% CI: -55.0-29.0%) after one year of follow-up. Similar levels and patterns of protection were observed irrespective of prior infection status, clinical vulnerability, or type of vaccine (BNT162b2 versus mRNA-1273). ConclusionsBoosters reduced infection and severe COVID-19, particularly among those clinically vulnerable to severe COVID-19. However, protection against infection waned after the booster, and eventually suggested an imprinting effect of compromised protection relative to the primary series. However, imprinting effects are unlikely to negate the overall public health value of booster vaccinations.

BACKGROUNDQatar has been experiencing a large SARS-CoV-2 Omicron (B.1.1.529) wave that started on December 19, 2021. We assessed duration of protection of BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines after second dose and after third/booster dose against symptomatic Omicron infection and against COVID-19 hospitalization and death, between December 23, 2021 and February 2, 2022. METHODSVaccine effectiveness was estimated using the test-negative, case-control study design, applying the same methodology used earlier to assess waning of BNT162b2 and mRNA-1273 effectiveness in the same population during earlier infection waves. RESULTSBNT162b2 effectiveness against symptomatic Omicron infection was highest at 61.9% (95% CI: 49.9-71.1%) in the first month after the second dose, but then gradually declined and was at 10% or less starting from the 5th month after the second dose. After the booster, effectiveness rapidly rebounded to peak at about 55% between 2-5 weeks after the booster, but then started to decline again thereafter. Effectiveness against severe, critical, or fatal COVID-19 was maintained at >70% after the second dose and at >90% after the booster with no evidence for declining effectiveness over time. mRNA-1273 effectiveness against symptomatic Omicron infection was highest at 44.8% (95% CI: 16.0-63.8%) in the first three months after the second dose, before gradually declining to negligible levels thereafter. After the booster, effectiveness rapidly rebounded to peak at about 55% between 2-5 weeks after the booster, but then declined again thereafter. Effectiveness against severe, critical, or fatal COVID-19 was high at >60% after the second dose and at >80% after the booster, but the confidence intervals were wide owing to the small number of cases. CONCLUSIONSBNT162b2 and mRNA-1273 vaccines show a similar level and pattern of protection against symptomatic Omicron infection. Protection against Omicron is lower than that against Alpha, Beta, and Delta variants, and wanes more rapidly than against earlier variants after the second and booster doses. Meanwhile, protection against hospitalization and death appears robust and durable after both the second and booster doses.

ImportanceDue to the emergence of highly transmissible SARS-CoV-2 variants, evaluation of boosters is needed. ObjectivesEvaluate safety and immunogenicity of 100-{micro}g of mRNA-1273 booster dose in adults. DesignOpen-label, Phase 2/3 study. SettingMulticenter study at 8 sites in the U.S. ParticipantsThe mRNA-1273 100-{micro}g booster was administered to adults who previously received a two dose primary series of 100-{micro}g mRNA-1273 in the phase 3 Coronavirus Efficacy (COVE) trial, at least 6 months earlier. InterventionLipid nanoparticle containing 100-{micro}g of mRNA encoding the spike glycoprotein of SARS-CoV-2 (Wuhan-HU-1). Main Outcomes and MeasuresSolicited local and systemic adverse reactions, and unsolicited adverse events were collected after vaccination. Primary immunogenicity objectives were to demonstrate non-inferiority of the neutralizing antibody (nAb) response against SARS-CoV-2 based on the geometric mean titer (GMTs) and the seroresponse rates (SRRs) (booster dose vs. primary series in a historical control group). nAbs against SARS-CoV-2 variants were also evaluated. ResultsThe 100-{micro}g booster dose had a greater incidence of local and systemic adverse reactions compared to the second dose of mRNA-1273 as well as the 50-{micro}g mRNA-1273 booster in separate studies. The geometric mean titers (GMTs; 95% CI) of SARS-CoV-2 nAbs against the ancestral SARS-CoV-2 at 28 days after the 100-{micro}g booster dose were 4039.5 (3592.7,4541.8) and 1132.0 (1046.7,1224.2) at 28 days after the second dose in the historical control group [GMT ratio=3.6 (3.1,4.2)]. SRRs (95% CI) were 100% (98.6,100) at 28 days after the booster and 98.1% (96.7,99.1) 28 days after the second dose in the historical control group [percentage difference=1.9% (0.4,3.3)]. The GMT ratio (GMR) and SRR difference for the booster as compared to the primary series met the pre-specified non-inferiority criteria. Delta-specific nAbs also increased (GMT fold-rise=233.3) after the 100-{micro}g booster of mRNA-1273. Conclusions and RelevanceThe 100-{micro}g mRNA-1273 booster induced a robust neutralizing antibody response against SARS-CoV-2, and reactogenicity was higher with the 100-{micro}g booster dose compared to the authorized booster dose level in adults (50-{micro}g). mRNA-1273 100-{micro}g booster dose can be considered when eliciting an antibody response might be challenging such as in moderately or severely immunocompromised hosts. Trial Registration: NCT04927065 Key PointsQuestion: What is the safety and immunogenicity of a booster dose of 100 {micro}g of mRNA-1273 in adults who previously received the primary series of mRNA-1273? Findings: In this open-label, Phase 2/3 study, the 100 {micro}g booster dose of mRNA-1273 had a greater incidence of local and systemic adverse reactions compared to a 50 {micro}g booster dose of mRNA- 1273 or after the second dose of mRNA-1273 during the primary series. The 100 {micro}g booster dose of mRNA-1273 induced a robust antibody response against the ancestral SARS-CoV-2 and variants. Meaning: mRNA-1273 100 {micro}g booster dose might be considered when eliciting an antibody response might be challenging, such as in moderately or severely immunocompromised hosts.

BackgroundVaccination with COVID-19 mRNA vaccines prevent hospitalization and severe disease caused by wildtype SARS-CoV-2 and several variants, and likely prevented infection when serum neutralizing antibody (NAb) titers were >1:160. Preventing infection limits viral replication resulting in mutation, which can lead to the emergence of additional variants. MethodsDuring a longitudinal study to evaluate durability of a three-dose mRNA vaccine regimen (2 primary doses and a booster) using a rapid test that semi-quantitatively measures NAbs, the Omicron variant emerged and quickly spread globally. We evaluated NAb levels measured prior to symptomatic breakthrough infection, in groups infected prior to and after the emergence of Omicron. ResultsDuring the SARS-CoV-2 Delta variant wave, 93% of breakthrough infections in our study occurred when serum NAb titers were <1:80. In contrast, after the emergence of Omicron, study participants with high NAb titers that had received booster vaccine doses became symptomatically infected. NAb titers prior to infection were [&ge;]1:640 in 64% of the Omicron-infected population, [&ge;]1:320 (14%), and [&ge;]1:160 (21%). DiscussionThese results indicate that high titers of NAbs elicited by currently available mRNA vaccines do not protect against infection with the Omicron variant, and that mild to moderate symptomatic infections did occur in a vaccinated and boosted population, although did not require hospitalization.

BackgroundThe highly transmissible severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron variant is a global concern. This study assessed the neutralization activity of two-dose regimens of mRNA-1273 vaccination against Omicron in adults, adolescents and children. MethodsNeutralizing activity against the Omicron variant was evaluated in serum samples from adults ([&ge;]18 years) in the phase 3, Coronavirus Efficacy (COVE) and from adolescents (12-17 years) in the TeenCOVE trials following a two-dose regimen of 100 {micro}g mRNA-1273 and from children (6-<12 years) in the KidCOVE trial administered two doses of 50 {micro}g mRNA-1273. Neutralizing antibody geometric mean ID50 titers (GMT) were measured using a lentivirus-based pseudovirus neutralizing assay at day 1 and 4 weeks (day 57) following the second mRNA-1273 dose, compared with wild-type (D614G). ResultsAt 4 weeks following a second dose of mRNA-1273 (100 {micro}g), the GMT was reduced 28.8-fold compared with D614G in adults ([&ge;]18 years). In adolescents (12-17 years), the GMT was 11.8-fold lower than D614G, 4 weeks after a second dose of mRNA-1273 (100 {micro}g), and compared with adults, were 1.5- and 3.8-fold higher for D614G and the Omicron variant, respectively. In children (6-<12 years), 4 weeks post-second dose of 50 {micro}g mRNA-1273, Omicron GMTs were reduced 22.1-fold versus D614G and were 2.0-fold higher for D614G and 2.5-fold higher for Omicron compared with adults. ConclusionsA two-dose regimen of 100 {micro}g mRNA-1273 in adolescents and of 50 {micro}g in children elicited neutralization responses against the Omicron variant that were reduced compared with the wild-type D614G, and numerically higher than those in adults.

Following a rise in cases due to the delta variant and evidence of waning immunity after 2 doses of the BNT162b2 vaccine, Israel began administering a third BNT162b2 dose (booster) in July 2021. Recent studies showed that the 3rd dose provides a much lower protection against infection with the omicron variant compared to the delta variant and that this protection wanes quickly. In this study, we used data from Israel to estimate the protection of the 3rd dose against severe disease up to 7 months from receiving the booster dose. The analysis shows that protection conferred by the 3rd dose against omicron did not wane over a 7-month period and that a 4th dose further increased protection, with a severe disease rate approximately 3-fold lower than in the 3-dose cohorts.

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.

We studied 249,070 patients who were tested for SARS-CoV-2 in the Cleveland Clinic Health System between October 1, 2021 and January 31, 2022. We found that vaccination, especially with recent boosting, was more effective than prior infection and monoclonal antibody therapy against both the delta and omicron variants. Vaccination and prior infection were much less effective against infection with the omicron variant than with the delta variant, but the opposite was true of death after infection. Boosting greatly increased the effectiveness of the two mRNA vaccines against both infection and death, although its effects waned markedly after 6 months. In addition, monoclonal antibody therapy was notably less effective at preventing death from the omicron variant than from the delta variant. Finally, the relatively low mortality of the omicron variant was due to both the reduced lethality of this variant and the increased population immunity acquired from booster vaccination and previous infection.

BackgroundSubvariants of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) omicron XBB-lineage have the potential to escape immunity provided by prior infection or vaccination. For Covid-19 immunizations beginning in the Fall 2023, the U.S. FDA has recommended updating to a monovalent omicron XBB.1.5-containing vaccine. MethodsIn this ongoing, phase 2/3 study participants were randomized 1:1 to receive 50-{micro}g doses of mRNA-1273.815 monovalent (50-{micro}g omicron XBB.1.5 spike mRNA) or mRNA-1273.231 bivalent (25-{micro}g omicron XBB.1.5 and 25-{micro}g omicron BA.4/BA.5 spike mRNAs) vaccines, administered as 5th doses, to adults who previously received a primary series and 3rd dose of an original mRNA coronavirus disease 2019 (Covid-19) vaccine, and a 4th dose of a bivalent (omicron BA.4/BA.5 and original SARS-CoV-2) vaccine. Interim safety and immunogenicity data 15 days post-vaccination are presented. ResultsIn April 2023, participants received mRNA-1273.815 (n=50) and mRNA-1273.231 (n=51). The median intervals from the prior dose of BA.4/BA.5-containing bivalent vaccine were 8.2 and 8.3 months for the mRNA-1273.815 and mRNA-1273.231 groups, respectively. Both vaccines increased neutralizing antibody (nAb) geometric mean titers against all variants tested at day 15 post-booster nAb compared to pre-booster levels. Geometric mean fold-rises from pre-booster titers after the monovalent booster were numerically higher against XBB.1.5, XBB.1.16 and SARS-CoV-2 (D614G) than those of the bivalent booster and were comparable against BA.4/BA.5 and BQ1.1 variants for both vaccines. The monovalent vaccine also elicited nAb responses against omicron XBB.2.3.2, EG.5.1, FL.1.5.1 and BA.2.86 that were similar to those against XBB.1.5 in a subset (n=20) of participants. The occurrence of solicited adverse reactions and unsolicited adverse events were overall similar to those previously reported for the original mRNA-1273 50-{micro}g and omicron BA.4/BA.5-containing bivalent mRNA-1273 vaccines. ConclusionIn this interim analysis, XBB.1.5-containing monovalent and bivalent vaccines elicited potent neutralizing responses against variants of the omicron XBB-lineage (XBB.1.5, XBB.1.6, XBB.2.3.2, EG.5.1, and FL.1.5.1) as well as the recently emerged BA.2.86 variant. The safety profile of the XBB.1.5-containing vaccine was consistent with those of prior vaccines. These results overall indicate that the XBB.1.5-containing mRNA-1273.815 vaccine has the potential to provide protection against these emerging variants and support the Covid-19 vaccine update in 2023-2024 to a monovalent XBB.1.5-containing vaccine.

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).

BackgroundFollowing emergency use authorization in December 2020, the Coronavirus Efficacy (COVE) trial was amended to an open-label phase, where participants were unblinded and those randomized to placebo were offered vaccination. Emergence of the delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with increased incidences of coronavirus disease 2019 (Covid-19) among unvaccinated and vaccinated persons. This exploratory analysis evaluated the incidence and genetic sequences of Covid-19 cases in the ongoing COVE trial during the open-label phase, with a focus on July-August 2021, when delta-variants surged in the US. MethodsCovid-19 cases were identified in participants initially randomized to mRNA-1273 (vaccinated from July-December 2020) and those initially randomized to the placebo (vaccinated December 2020-April 2021) who received at least one dose and were SARS-CoV-2-negative at baseline in the modified-intent-to-treat population were analyzed. Included were Covid-19 cases occurring after 26-Mar-2021 with positive RT-PCR results in nasopharyngeal samples (central lab test) and reported Covid-19 symptoms. Genetic sequencing of Covid-19 cases was also performed. ResultsThere were 14,746 participants in the earlier mRNA-1273 (mRNA-1273e) group and 11,431 in the later placebo-mRNA1273 (mRNA-1273p) group. Covid-19 cases increased from the start of the open-label phase to July-August 2021. During July and August, 162 Covid-19 cases occurred in the mRNA-1273e group and 88 in the mRNA-1273p group. Of the cases sequenced, 144/149 [97%]) in the mRNA-1273 and 86/88 (99%) in the mRNA-1273p groups were attributed to delta. The incidence rate of Covid-19 was lower for the mRNA-1273p (49.0/1000 person-years) versus mRNA-1273e (77.1/1000 person-years) group [36.4% (95% CI 17.1%-51.5%) reduction]. There were fewer severe Covid-19 cases in the mRNA-1273p (6; 6.2/1000 person-years) than mRNA-1273e (13; 3.3/1000 person-years) [46.0% (95% CI -52.4%-83.2%) reduction]. Three Covid-19 related hospitalizations occurred with two resulting deaths in the mRNA-1273e group. ConclusionIncidence rates of Covid-19 and severe Covid-19 were lower during the months when delta was the dominant variant (July/August 2021) among COVE participants vaccinated more recently. Analysis of COVID-19 cases from the open-label phase of the COVE study is ongoing.

Antibody responses against the SARS-CoV-2 Spike protein correlate with protection against COVID-19. Serum neutralizing antibodies appear early after symptom onset following SARS-CoV-2 infection and can last for several months. Similarly, the messenger RNA vaccine, mRNA-1273, generates serum neutralizing antibodies that are detected through at least day 119. However, the recent emergence of the B.1.1.7 variant has raised significant concerns about the breadth of these neutralizing antibody responses. In this study, we used a live virus neutralization assay to compare the neutralization potency of sera from infected and vaccinated individuals against a panel of SARS-CoV-2 variants, including SARS-CoV-2 B.1.1.7. We found that both infection- and vaccine-induced antibodies were effective at neutralizing the SARS-CoV-2 B.1.1.7 variant. These findings support the notion that in the context of the UK variant, vaccine-induced immunity can provide protection against COVID-19. As additional SARS-CoV-2 viral variants continue to emerge, it is crucial to monitor their impact on neutralizing antibody responses following infection and vaccination.

BackgroundCoronavirus Disease 2019 (COVID-19) vaccine antigen dosage may affect protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but direct evidence to quantify this effect is lacking. MethodsA matched, retrospective, cohort study that emulated a randomized control trial was conducted in Qatar between February 3, 2022 and November 8, 2022, to provide a head-to-head, controlled comparison of protection induced by two antigen dosages of the BNT162b2 vaccine. The study compared incidence of omicron infection in the national cohort of adolescents 12 years of age who received the two-dose primary-series of the 30-{micro}g BNT162b2 vaccine to that in the national cohort of adolescents 11 years of age who received the two-dose primary-series of the pediatric 10-{micro}g BNT162b2 vaccine. Associations were estimated using Cox proportional-hazard regression models. ResultsAmong adolescents with no record of prior infection, cumulative incidence of infection was 6.0% (95% CI: 4.9-7.3%) for the 30-{micro}g cohort and 7.2% (95% CI: 6.1-8.5%) for the 10-{micro}g cohort, 210 days after the start of follow-up. Incidence during follow-up was dominated by omicron subvariants including, consecutively, BA.1/BA.2, BA.4/BA.5, BA.2.75*, and XBB. The adjusted hazard ratio comparing incidence of infection in the 30-{micro}g cohort to the 10-{micro}g cohort was 0.77 (95% CI: 0.60-0.98). Corresponding relative effectiveness was 23.4% (95% CI: 1.6-40.4%). Relative effectiveness was -3.3% (95% CI: -68.0-27.5%) among adolescents with a record of prior infection. ConclusionsThree-fold higher BNT162b2 dosage was associated with [~]25% higher protection against infection in infection-naive adolescents of similar age. These findings may inform design of future COVID-19 vaccines and boosters for persons of different age groups.

The SARS-CoV-2 vaccine BBV152/Covaxin is well-tolerated and was shown to be 77.8% efficacious against symptomatic and 93.4% efficacious against severe symptomatic COVID-19 disease in adults. Previous studies have shown that sera from Covaxin vaccinated individuals have neutralizing activity against B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), B.1.1.28 (Zeta), and B.1.617.1 (Kappa) SARS-CoV-2 variants. The B.1.1.529 variant (Omicron) recently emerged in November 2021 and has spread throughout the world. The Omicron variant has more than 30 mutations within the spike protein that could impact vaccine-mediated immunity. We used a live virus neutralization assay to evaluate the neutralizing activity against the Omicron variant of sera collected from subjects who received a booster dose (6-month after primary series last dose) of Covaxin. We found that sera from Covaxin boosted individuals showed neutralizing activity against D614G (vaccine strain), Delta, and Omicron variants. One hundred percent of boosted subjects showed neutralizing activity against the Delta variant while over 90% of boosted subjects showed neutralizing activity against the Omicron variant. These findings show that a booster dose of Covaxin can generate robust neutralizing antibody responses against the Omicron variant.

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.

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)