Neutralizing Antibody Geometric Mean Titers Research Articles

The impact of early anti-SARS-CoV-2 antibody production on the length of hospitalization stay among COVID-19 patients.

COVID-19 has challenged the scientific community in the search for biological markers and information that can contribute to the early management of the severe disease. Given the global scale of COVID-19, including reports of reinfection even in the presence of effective vaccines; consequently, the eradication of SARS-CoV-2 is far from happening. This study aimed to characterize the neutralizing antibody (Nab) geometric mean titers (GMTs) in hospitalized patients with COVID-19 and to evaluate the association with length of stay, comorbidities, and patient outcome. Among the 103 participants, 84 (81.5%) had some previous conditions associated with worsening health and 34 (33%) died. We found that neutralization potency varied greatly across individuals and was significantly higher in patients discharged before 14 days than in patients who stayed longer in the hospital. During the study period, 15 people living with HIV (PLWH) were hospitalized, and no significant difference in clinical characteristics or anti-SARS-CoV-2 Nabs was observed. However, PLWH with severe COVID-19 were younger [42, interquartile range (IQR) = 17.5] than other hospitalized COVID-19 patients (59, IQR = 22, P < 0.01). A high anti-HIV-1 antibody GMT of 583.9 (95% confidence interval: 344-990) was detected, demonstrating maintenance of anti-HIV-1 Nab production among PLWH coinfected with SARS-CoV-2. Therefore, these results indicate that neutralizing antibodies are not the only immunological response capable of controlling disease progression, but a high neutralizing response was associated with a shorter length of stay, suggesting the benefit of early-stage immunotherapy treatment of COVID-19. Nevertheless, these data highlight the importance of more Nab screening studies to predict faster recovery.IMPORTANCEThe study provides valuable insights into the sociodemographic characteristics, clinical outcomes, and humoral immune response of those affected by the virus that has devastated every field of human life since 2019; the COVID-19 patients. Firstly, the association among clinical manifestations, comorbidities, and the production of neutralizing antibodies (Nabs) against SARS-CoV-2 is explored. Secondly, varying levels of Nabs among patients are revealed, and a significant correlation between the presence of Nabs and a shorter duration of hospitalization is identified, which highlights the potential role of Nabs in predicting clinical outcomes. Lastly, a follow-up conducted 7 months later demonstrates the progression and persistence of Nabs production in recovered unvaccinated individuals. The study contributes essential knowledge regarding the characteristics of the study population, the early humoral immune response, and the dynamics of Nabs production over time. These findings have significant implications for understanding the immune response to COVID-19 and informing clinical management approaches.

The 6-Month Antibody Durability of Heterologous Convidecia Plus CoronaVac and Homologous CoronaVac Immunizations in People Aged 18-59 Years and over 60 Years Based on Two Randomized Controlled Trials in China.

Previous reports have shown that heterologous boosting with the AD5-vectored COVID-19 vaccine Convidecia based on a primary series of two doses of inactivated vaccine induces increasing immune responses. However, the immune persistence until 6 months after the heterologous prime-boost immunization was limited. Participants were from two single-center, randomized, controlled, observer-blinded trials, which involved individuals of 18-59 years of age and over 60 years of age. Eligible participants who previously primed with one dose or two doses of CoronaVac were stratified and randomly assigned to inoculate a booster dose of Convidecia or CoronaVac. Neutralizing antibodies against a live SARS-CoV-2 prototype virus and Delta and Omicron (B.1.1.529) variants, pseudovirus neutralizing antibodies against Omicron BA.4/5 variants, and anti-SARS-CoV-2 RBD antibodies at month 6 were detected, and the fold decreases and rate difference were calculated by comparing the levels of antibodies at month 6 with the peak levels at month 1. The neutralizing antibody titers against prototype SARS-CoV-2, RBD-specific IgG antibodies, and the Delta variant in the heterologous regimen of the CoronaVac plus Convidecia groups were significantly higher than those of the homologous prime-boost groups. In three-dose regimen groups, the geometric mean titers (GMTs) of neutralizing antibodies against prototype SARS-CoV-2 were 30.6 (95% CI: 25.1; 37.2) in the heterologous boosting group versus 6.9 (95% CI: 5.6; 8.6) in the homologous boosting group (p < 0.001) at month 6 in participants aged 18-59 years, and in the two-dose regimen, the neutralizing antibody GMTs were 8.5 (95% CI: 6.2; 11.7) and 2.7 (2.3 to 3.1) (heterologous regimen group versus CoronaVac regimen group, p < 0.001). Participants aged over 60 years had similar levels of neutralizing antibodies against the prototype, with GMTs of 49.1 (38.0 to 63.6) in the group receiving two doses of CoronaVac plus one dose of Convidecia versus 9.4 (7.7 to 11.4) in the group receiving three doses of CoronaVac (p < 0.001) and 11.6 (8.4 to 16.0) in the group receiving one dose of CoronaVac and one dose of Convidecia versus 3.3 (2.7 to 4.0) in the group receiving two doses of CoronaVac (p < 0.001). Compared with day 14, over sixfold decreases in neutralizing antibody GMTs were observed in the heterologous groups of the three- or two-dose regimen groups of younger and elderly participants, while in the homologous regimen groups, the GMTs of neutralizing antibodies decreased about fivefold in the two age groups. The heterologous prime-boost regimen with two doses of CoronaVac and one dose of Convidecia was persistently more immunogenic than the regimen of the homologous prime-boost with three doses of CoronaVac.

Safety and Immunogenicity of Inactivated Whole Virion COVID-19 Vaccine CoviVac in Clinical Trials in 18-60 and 60+ Age Cohorts.

We present the results of a randomized, double-blind, placebo-controlled, multi-center clinical trial phase I/II of the tolerability, safety, and immunogenicity of the inactivated whole virion concentrated purified coronavirus vaccine CoviVac in volunteers aged 18-60 and open multi-center comparative phase IIb clinical trial in volunteers aged 60 years and older. The safety of the vaccine was assessed in 400 volunteers in the 18-60 age cohort who received two doses of the vaccine (n = 300) or placebo (n = 100) and in 200 volunteers in 60+ age cohort all of whom received three doses of the vaccine. The studied vaccine has shown good tolerability and safety. No deaths, serious adverse events (AEs), or other significant AEs related to vaccination have been detected. The most common AE in vaccinated participants was pain at the injection site (p < 0.05). Immunogenicity assessment in stage 3 of Phase II was performed on 167 volunteers (122 vaccinated and 45 in Placebo Group) separately for the participants who were anti-SARS-CoV-2 nAB negative (69/122 in Vaccine Group and 28/45 in Placebo Group) or positive (53/122 in Vaccine Group and 17/45 in Placebo Group) at screening. On Day 42 after the 1st vaccination, the seroconversion rate in participants who were seronegative at screening was 86.9%, with the average geometric mean neutralizing antibody (nAB) titer of 1:20. A statistically significant (p < 0.05) increase in IFN-γ production by peptide-stimulated T-cells was observed at Days 14 and 21 after the 1st vaccination. In participants who were seropositive at screening but had nAB titers below 1:256, the rate of fourfold increase in nAB levels was 85.2%, while in the participants with nAB titers > 1:256, the rate of fourfold increase in nAB levels was below 45%; the participants who were seropositive at screening of the 2nd vaccination did not lead to a significant increase in nAB titers. In conclusion, inactivated vaccine CoviVac has shown good tolerability and safety, with over 85% NT seroconversion rates after complete vaccination course in participants who were seronegative at screening in both age groups: 18-60 and 60+. In participants who were seropositive at screening and had nAB titers below 1:256, a single vaccination led to a fourfold increase in nAB levels in 85.2% of cases. These findings indicate that CoviVac can be successfully used both for primary vaccination in a two-dose regimen and for booster vaccination as a single dose in individuals with reduced neutralizing antibody levels.

Immunogenicity and reactogenicity of heterologous COVID-19 vaccination in pregnant women

ABSTRACT This open-labeled non-inferiority trial evaluated immunogenicity and reactogenicity of heterologous and homologous COVID-19 vaccination schedules in pregnant Thai women. 18–45-year-old pregnant women with no history of COVID-19 infection or vaccination and a gestational age of ≥12 weeks were randomized 1:1:1 into three two-dose primary series scheduled 4 weeks apart: BNT162b2-BNT162b2 (Group 1), ChAdOx1-BNT162b2 (Group 2), and CoronaVac-BNT162b2 (Group 3). Serum antibody responses, maternal and cord blood antibody levels at delivery, and adverse events (AEs) following vaccination until delivery were assessed. The 124 enrolled participants had a median age of 31 (interquartile range [IQR] 26.0–35.5) years and gestational age of 23.5 (IQR 18.0–30.0) weeks. No significant difference in anti-receptor binding domain (RBD) IgG were observed across arms at 2 weeks after the second dose. Neutralizing antibody geometric mean titers against the ancestral Wuhan strain were highest in Group 3 (258.22, 95% CI [187.53, 355.56]), followed by Groups 1 (187.47, 95% CI [135.15, 260.03]) and 2 (166.63, 95% CI [124.60, 222.84]). Cord blood anti-RBD IgG was correlated with, and equal to or higher than, maternal levels at delivery (r = 0.719, P < .001) and inversely correlated with elapsed time after the second vaccination (r = −0.366, P < .001). No significant difference in cord blood antibody levels between groups were observed. Local and systemic AEs were mild-to-moderate and more frequent in Group 2. Heterologous schedules of CoronaVac-BNT162b2 or ChAdOx1-BNT162b2 induced immunogenicity on-par with BNT162b2-BNT162b2 and may be considered as alternative schedules for primary series in pregnant women in mRNA-limited vaccine settings.

Anti-RBD IgG antibodies and neutralizing antibody levels after the second BNT162b2 dose in patients with plasma cell disorders.

Patients with plasma cell disorders (PCD) are at an increased risk for severe morbidity and mortality due to COVID-19. Recent data have suggested that patients with hematological malignancies, including those with PCD, have suboptimal antibody response to COVID-19 vaccination. We compared the antibody titers of 213 patients with PCD to those of 213 immunocompetent healthcare workers after the second vaccine dose of the BNT162b2 mRNA vaccine. Blood samples were taken 2-4 weeks after the second vaccination and analyzed for anti-receptor binding-domain immunoglobulin G (RBD-IgG) antibodies and neutralizing antibodies (NA). At a median of 20 days after the second vaccine dose, 172 patients (80.8%) developed anti-RBD-IgG antibodies with a geometric mean titer (GMT) of 2.7 (95% confidence interval [CI], 2.4-3.1). In the control group 210 (98.9%) developed anti-RBD-IgG antibodies after a median of 21 days, with a GMT of 5.17 (95%CI, 4.8-5.6), p<0.0001. NA were observed in 151 patients with MM (70.9%) and in 210 controls (98.9%). The GMT of NA in patients with MM and controls was 84.4 (95% CI, 59.0-120.6), and 420.2 (95% CI, 341.4-517.1), respectively (p<0.0001). Multivariable logistic regression revealed that the number of prior therapy lines and age were significant predictors of poor humoral response among patients with MM. Injection site reaction, headache and fatigue were the most common adverse events after vaccination. Adverse events were less common in patients with MM than in controls. In conclusion, a significant percentage of patients with MM developed protecting NA to the BNT162b2 mRNA vaccine, which appears to be safe in this patient population.

Safety, Immunogenicity, and Efficacy of the NVX-CoV2373 COVID-19 Vaccine in Adolescents

Greater than 20% of cases and 0.4% of deaths from COVID-19 occur in children. Following demonstration of the safety and efficacy of the adjuvanted, recombinant spike protein vaccine NVX-CoV2373 in adults, the PREVENT-19 trial immediately expanded to adolescents. To evaluate the safety, immunogenicity, and efficacy of NVX-CoV2373 in adolescents. The NVX-CoV2373 vaccine was evaluated in adolescents aged 12 to 17 years in an expansion of PREVENT-19, a phase 3, randomized, observer-blinded, placebo-controlled multicenter clinical trial in the US. Participants were enrolled from April 26 to June 5, 2021, and the study is ongoing. A blinded crossover was implemented after 2 months of safety follow-up to offer active vaccine to all participants. Key exclusion criteria included known previous laboratory-confirmed SARS-CoV-2 infection or known immunosuppression. Of 2304 participants assessed for eligibility, 57 were excluded and 2247 were randomized. Participants were randomized 2:1 to 2 intramuscular injections of NVX-CoV2373 or placebo, 21 days apart. Serologic noninferiority of neutralizing antibody responses compared with those in young adults (aged 18-25 years) in PREVENT-19, protective efficacy against laboratory-confirmed COVID-19, and assessment of reactogenicity and safety. Among 2232 participants (1487 NVX-CoV2373 and 745 placebo recipients), the mean (SD) age was 13.8 (1.4) years, 1172 (52.5%) were male, 1660 (74.4%) were White individuals, and 359 (16.1%) had had a previous SARS-CoV-2 infection at baseline. After vaccination, the ratio of neutralizing antibody geometric mean titers in adolescents compared with those in young adults was 1.5 (95% CI, 1.3-1.7). Twenty mild COVID-19 cases occurred after a median of 64 (IQR, 57-69) days of follow-up, including 6 among NVX-CoV2373 recipients (incidence, 2.90 [95% CI, 1.31-6.46] cases per 100 person-years) and 14 among placebo recipients (incidence, 14.20 [95% CI, 8.42-23.93] cases per 100 person-years), yielding a vaccine efficacy of 79.5% (95% CI, 46.8%-92.1%). Vaccine efficacy for the Delta variant (the only viral variant identified by sequencing [n = 11]) was 82.0% (95% CI, 32.4%-95.2%). Reactogenicity was largely mild to moderate and transient, with a trend toward greater frequency after the second dose of NVX-CoV2373. Serious adverse events were rare and balanced between treatments. No adverse events led to study discontinuation. The findings of this randomized clinical trial indicate that NVX-CoV2373 is safe, immunogenic, and efficacious in preventing COVID-19, including the predominant Delta variant, in adolescents. ClinicalTrials.gov Identifier: NCT04611802.

Safety, reactogenicity, and immunogenicity of Ad26.COV2.S: Results of a phase 1, randomized, double-blind, placebo-controlled COVID-19 vaccine trial in Japan.

This study evaluated safety, reactogenicity, and immunogenicity of a 2-month homologous booster regimen of Ad26.COV2.S in Japanese adults. In this multicenter, placebo-controlled, Phase 1 trial, adults (Cohort 1, aged 20-55years, N=125; Cohort 2, aged≥65years, N=125) were randomized 2:2:1 to receive Ad26.COV2.S 5×1010 viral particles (vp), Ad26.COV2.S 1×1011 vp, or placebo, followed by a homologous booster 56days later. Safety, reactogenicity, and immunogenicity were assessed. Two hundred participants received Ad26.COV2.S and 50 received placebo. The most frequent solicited local adverse event (AE) was vaccination-site pain, and the most frequent solicited systemic AEs were fatigue, myalgia, and headache. After primary vaccination, neutralizing and binding antibody levels increased through Day 57 (post-prime) in both cohorts. Fourteen days after boosting (Day 71), neutralizing antibody geometric mean titers (GMTs) had almost reached their peak value in Cohort 1 (5×1010 vp: GMT=1049; 1×1011 vp: GMT=1470) and peaked in Cohort 2 (504; 651); at Day 85, GMTs had declined minimally in Cohort 2. For both cohorts, binding antibody levels peaked at Day 71 with minimal decline at Day 85. A single dose and homologous Ad26.COV2.S booster increased antibody responses with an acceptable safety profile in Japanese adults (ClinicalTrials.gov Identifier: NCT04509947).

Safety and immunogenicity of a mosaic vaccine booster against Omicron and other SARS-CoV-2 variants: a randomized phase 2 trial

An ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of a mosaic-type recombinant vaccine candidate, named NVSI-06-09, as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had administered two or three doses of inactivated vaccine BBIBP-CorV at least 6 months prior to enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. Between May 25 and 30, 2022, 516 adults received booster vaccination with 260 in NVSI-06-09 group and 256 in BBIBP-CorV group. Interim results showed a similar safety profile between two booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 post-booster, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those by BBIBP-CorV. Our findings indicated that a booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against divergent SARS-CoV-2 variants, including Omicron and its sub-lineages.

2139. Immunogenicity, reactogenicity and safety of a Respiratory Syncytial Virus prefusion F (RSVPreF3) candidate vaccine co-administered with the seasonal quadrivalent influenza vaccine in older adults

Abstract Background Respiratory syncytial virus (RSV) can cause severe respiratory disease in older adults (OAs). However, there is no approved vaccine against RSV disease in OAs. Co-administration of vaccines against RSV and influenza could be considered given their overlapping seasonality. Here, we assessed the immunogenicity, reactogenicity and safety of an RSV prefusion F Older Adult (RSVPreF3 OA) investigational vaccine when co-administered with the seasonal quadrivalent influenza vaccine (FLU-QIV) in OAs. Methods In this Phase 3, open-label, controlled, multi-country study (NCT04841577), OAs aged ≥ 60 years recruited in New Zealand, Panama and South Africa were randomized 1:1 to receive either RSVPreF3 OA and FLU-QIV simultaneously on day 1 (Co-Ad group), or FLU-QIV on day 1 and RSVPreF3 OA on day 31 (Control group). The co-primary objectives were to demonstrate the non-inferiority of i) RSVPreF3 OA in terms of RSV-A neutralizing antibody geometric mean titers (GMT) ratio and ii) FLU-QIV in terms of hemagglutinin inhibition antibody GMT ratio for each Flu strain when co-administered versus when administered alone. Blood samples were collected from all participants pre vaccination and 1 month post vaccination. Non-inferiority was demonstrated if the upper limit (UL) of the 95% confidence interval (CI) of the group GMT ratio (Control/Co-Ad) was ≤ 1.5. Secondary descriptive outcomes included reactogenicity and safety. Results 885 participants received at least 1 dose of the study interventions. Of these, 838 were included in the per protocol set at 1 month post vaccination. The demographic characteristics of the participants were similar across groups. The study co-primary objectives were met; for both vaccines, the UL of the 95% CI of the GMT ratio was ≤ 1.5 (Table 1). The observed safety events were balanced between Co-Ad and Control groups (Table 2). The reactogenicity profile of the Co-ad group compared with the Control group was driven by the RSVPreF3 OA investigational vaccine. Conclusion Our results support simultaneous seasonal vaccination with RSVPreF3 OA and FLU-QIV in adults ≥ 60 years, as co-administration elicits a statistically non-inferior immune response to the administration of each vaccine alone, with no safety concerns identified. Disclosures Nathali Montenegro, MD, GSK: Support for the present abstract/study Lorena Noriega-Aguirre, MD, ScD, Astra Zeneca: Advisor/Consultant|Astra Zeneca: Honoraria|Astra Zeneca: Support for attending meetings and/or travel|Boehringer Ingelheim: Honoraria|Boehringer Ingelheim: Support for attending meetings and/or travel|GSK: Advisor/Consultant|GSK: Support for the present abstract/study|Novartis: Honoraria Mohammed Bensellam, PhD, GlaxoSmithKline Biologicals SA: Agency worker on assignment at GSK Nathalie De Schrevel, PhD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Ownership Interest Sherine Kuriyakose, MSc, GSK: GSK Employee Axel Lambert, MSc, GSK: GSK Employee Aurélie Olivier, PhD, GlaxoSmithKline Biologicals SA: I’m an employee of GSK Biologicals|GlaxoSmithKline Biologicals SA: Ownership Interest Veronica Hulstrøm, PhD MD, GlaxoSmithKline Biologicals SA: Employee.

96. A Candidate Respiratory Syncytial Virus (RSV) Prefusion F Protein Investigational Vaccine (RSVPreF3 OA) Is Immunogenic when Administered in Adults ≥ 60 Years of Age: Results at 6 Months after Vaccination

Abstract Background RSV infections are frequent and can lead to respiratory complications in older adults (OA). However, there is no licensed RSV vaccine yet. Here we present immunogenicity results up to month (M) 6 after vaccination with the RSVPreF3 OA. Methods In this phase 3 multi-country ongoing study (NCT04732871), adults ≥ 60 years of age were randomized (3:1:1) to receive RSVPreF3 OA and to be followed up for 3 years. All participants received a dose of RSVPreF3 on day (D) 1. Humoral immune (HI) and cell-mediated immune (CMI) responses were measured in subsets of participants at pre-vaccination (D1), D31 and M6. HI outcomes included RSV-A and RSV-B neutralizing antibody (NAb) geometric mean titers (GMTs) and RSVPreF3-specific immunoglobulin G (IgG) antibody geometric mean concentrations (GMCs). The CMI response was assessed in terms of frequency of RSVPreF3-specific CD4+ T-cells and CD8+ T-cells expressing at least 2 activation markers including at least 1 cytokine among CD40L, 4-1BB, IL-2, TNF-α, IFN-γ, IL-13, IL-17 (polypositive T-cells). Results A total of 1653 participants received a dose of RSVPreF3 OA. Of these, 987 participants were included in the HI subset and 566 in the CMI subset at D1. The RSV-A and RSV-B GMTs and RSVPreF3-specific IgG GMCs increased between D1 and D31 followed by a decline until M6. At D31, RSV-A and RSV-B NAb GMTs were 10.5-fold and 7.8-fold higher than pre-vaccination (Figure), and RSVPreF3-specific IgG antibody GMCs was 12.2-fold higher than pre-vaccination levels. At M6, the RSV-A and RSV-B GMTs were 4.4-fold and 3.5-fold, and RSVPreF3-specific IgG antibody GMCs were 4.7-fold above pre-vaccination levels. The RSVPreF3-specific polypositive CD4+ T-cell median frequency (events/106 cells) increased from 191 (below assay quantification limit) to 1339 at D31 and declined to 666 (above assay quantification limit) by M6. No RSVPreF3-specific CD8+ T-cell response was detected after RSVPreF3 OA vaccination. Conclusion In adults ≥ 60 years of age, 1 dose of RSVPreF3 OA was shown to be immunogenic, with both high HI and specific CMI responses at D31 post-vaccination and remained 3.5–4.7 fold above pre-vaccination levels at M6. This study will continue to monitor the immunogenicity of RSVPreF3 OA up to 3 years. Funding GlaxoSmithKline Biologicals SA. Disclosures Tino F. Schwarz, Prof. Dr. MD, Biogen, Merck-Serono, Pfizer, Alexion, Bavarian Nordic, Janssen-Cilag, AstraZeneca, Biontech, MSD: Grants|GlaxoSmithKline Biologicals SA: Honoraria John E. Ervin, MD, The Alliance for Multispecialty Research – KCM: Contractual agreement for conduct of study protocol Charles Andrews, MD, GlaxoSmithKline Biologicals SA: Institutional grant|Merck and Boehringer Ingelheim: Consulting fees outside of the submitted work Delphine Collete, PhD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Magali de Heusch, PhD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Nathalie De Schrevel, PhD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Ownership Interest Bruno Salaun, PhD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Marc Lievens, MSc, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Céline Maréchal, PhD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Phoebe Nakanwagi, Master’s in Biostatistics, GlaxoSmithKline Biologicals SA: Employee Veronica Hulstrøm, PhD MD, GlaxoSmithKline Biologicals SA: Employee.

Durability of ChAdOx1 nCoV-19 (AZD1222) vaccine and hybrid humoral immunity against variants including omicron BA.1 and BA.4 6 months after vaccination (COV005): a post-hoc analysis of a randomised, phase 1b–2a trial

BackgroundCOVID-19 vaccine rollout is lagging in Africa, where there has been a high rate of SARS-CoV-2 infection. We aimed to evaluate the effect of SARS-CoV-2 infection before vaccination with the ChAdOx-nCoV19 (AZD1222) vaccine on antibody responses through to 180 days.MethodsWe did an unmasked post-hoc immunogenicity analysis after the first and second doses of AZD1222 in a randomised, placebo-controlled, phase 1b–2a study done in seven locations in South Africa. AZD1222 recipients who were HIV-uninfected, were stratified into baseline seropositive or seronegative groups using the serum anti-nucleocapsid (anti-N) immunoglobulin G (IgG) electroluminescence immunoassay to establish SARS-CoV-2 infection before the first dose of AZD1222. Binding IgG to spike (anti-S) and receptor binding domain (anti-RBD) were measured before the first dose (day 0), second dose (day 28), day 42, and day 180. Neutralising antibody (NAb) against SARS-CoV-2 variants D614G, beta, delta, gamma, and A.VOI.V2, and omicron BA1 and BA.4 variants, were measured by pseudovirus assay (day 28, day 42, and day 180). This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132.FindingsOf 185 individuals who were randomly assigned to AZD1222, we included 91 individuals who were baseline seropositive and 58 who were baseline seronegative, in the final analysis. In the seropositive group, there was little change of anti-S IgG (and anti-RBD IgG) or neutralising antibody (NAb) titres at day 42 compared with at day 28. Anti-S (and anti-RBD) IgG geometric mean concentrations (GMCs) were higher throughout in the seropositive compared with the seronegative group, including at day 180 (GMCs 517·8 [95% CI 411·3–651·9] vs 82·1 [55·2–122·3] BAU/mL). Also D614G NAb geometric mean titres (GMTs) were higher in the seropositive group than the seronegative group, as was the percentage with titres of at least 185 (80% putative risk reduction threshold [PRRT] against wild-type–alpha COVID-19), including at day 180 (92·0% [74·0–99·0] vs 18·2% [2·3–51·8). Similar findings were observed for beta, A.VOI.V2, and gamma. For delta, BA.1, and BA.4, NAb GMTs and the proportion with titres above the PRRT were substantially higher in the seropositive compared with seronegative group at day 28 and day 42, but no longer differed between the groups by day 180.InterpretationA single dose of AZD1222 in the general African population, where COVID-19 vaccine coverage is low and SARS-CoV-2 seropositivity is 90%, could enhance the magnitude and quality of antibody responses to SARS-CoV-2.FundingThe Bill & Melinda Gates Foundation, the South African Medical Research Council, the UK Research and Innovation, the UK National Institute for Health Research, and the South African Medical Research Council.TranslationFor the Zulu translation of the abstract see Supplementary Materials section.

Associations of Immunogenicity and Reactogenicity After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA-1273 Vaccine in the COVE and TeenCOVE Trials.

The reactogenicity and immunogenicity of coronavirus disease 2019 (COVID-19) vaccines are well studied. Little is known regarding the relationship between immunogenicity and reactogenicity of COVID-19 vaccines. This study assessed the association between immunogenicity and reactogenicity after 2 mRNA-1273 (100 µg) injections in 1671 total adolescent and adult participants (≥12 years) from the primary immunogenicity sets of the blinded periods of the Coronavirus Efficacy (COVE) and TeenCOVE trials. Associations between immunogenicity through day 57 and solicited adverse reactions (ARs) after the first and second injections of mRNA-1273 were evaluated among participants with and without solicited ARs using linear mixed-effects models. mRNA-1273 reactogenicity in this combined analysis set was similar to that reported for these trials. The vaccine elicited high neutralizing antibody (nAb) geometric mean titers (GMTs) in evaluable participants. GMTs at day 57 were significantly higher in participants who experienced solicited systemic ARs after the second injection (1227.2 [1164.4-1293.5]) than those who did not (980.1 [886.8-1083.2], P = .001) and were associated with fever, chills, headache, fatigue, myalgia, and arthralgia. Significant associations with local ARs were not found. These data show an association of systemic ARs with increased nAb titers following a second mRNA-1273 injection. While these data indicate systemic ARs are associated with increased antibody titers, high nAb titers were observed in participants after both injections, consistent with the immunogenicity and efficacy in these trials. These results add to the body of evidence regarding the relationship of immunogenicity and reactogenicity and can contribute toward the design of future mRNA vaccines.

Immunogenicity and safety of third-dose mRNA COVID-19 vaccines in healthy adults previously vaccinated with two doses of the ChAdOx1 vaccine

Background/Purpose: The efficacy and safety of coronavirus disease 2019 (COVID-19) booster vaccines remain limited. We investigated the immunogenicity and adverse events of the third dose of mRNA vaccines in healthy adults.MethodsVolunteers vaccinated with two doses of the adenoviral vaccine (ChAdOx1) 12 weeks before were administered with an mRNA COVID-19 vaccine. These were divided into three groups, full-dose mRNA-1273 (group 1); half-dose mRNA-1273 (group 2); and full-dose BNT-162b2 (group 3). Primary outcomes included serum anti-SARS-CoV-2 spike immunoglobulin G (IgG) titers and neutralizing antibody titers against B.1.1.7 (alpha), B.1.617.2 (delta), and B.1.1.529 (omicron) variants. Secondary outcomes included the evaluation of humoral and cellular immunity and vaccine-associated adverse events after the boost.ResultsTotally 300 participants were recruited, and 298 participants were enrolled. For all three groups, an increase in anti-SARS-CoV-2 spike IgG geometric mean titers (30.12- to 71.81-fold) and neutralizing antibody titers against the alpha variant (69.77- to 173.2-folds), delta variant (132.68- to 324.73-folds), and omicron variant (135.4- to 222.4-folds) were observed on day 28. All groups showed robust T- and B-cell responses after boosting. Adverse events were overall mild and transient but with higher prevalence and severity in group 1 participants than in other groups.ConclusionsThird dose mRNA COVID-19 vaccines markedly enhanced cellular and humoral responses and were safe. Immunological responses and adverse events were higher in individuals receiving the full-dose mRNA-1273 vaccine, followed by a half-dose mRNA-1273 vaccine and BNT-162b2 vaccine.

Safety and immunogenicity of PXVX0317, an aluminium hydroxide-adjuvanted chikungunya virus-like particle vaccine: a randomised, double-blind, parallel-group, phase 2 trial

Chikungunya virus (CHIKV) disease is an ongoing public health threat. We aimed to evaluate the safety and immunogenicity of PXVX0317, an aluminium hydroxide-adjuvanted formulation of a CHIKV virus-like particle (VLP) vaccine. This randomised, double-blind, parallel-group, phase 2 trial was conducted at three clinical trial centres in the USA. Eligible participants were healthy CHIKV-naïve adults aged 18-45 years. Participants were stratified by site and randomly assigned (1:1:1:1:1:1:1:1) to one of the eight vaccination groups using a block size of 16. Group 1 received two doses of unadjuvanted PXVX0317 28 days apart (2 × 20 μg; standard); all other groups received adjuvanted PXVX0317: groups 2-4 received two doses 28 days apart (2 × 6 μg [group 2], 2 × 10 μg [group 3], or 2 × 20 μg [group 4]; standard); group 4 also received a booster dose 18 months after the first active injection (40 μg; standard plus booster); groups 5-7 received two doses 14 days apart (2 × 6 μg [group 5], 2 × 10 μg [group 6], or 2 × 20 μg [group 7]; accelerated); and group 8 received one dose (1 × 40 μg; single). The primary endpoint was the geometric mean titre of anti-CHIKV neutralising antibody on day 57 (28 days after the last vaccination), assessed in the immunogenicity-evaluable population. Additionally, we assessed safety. This trial is registered at ClinicalTrials.gov, NCT03483961. This trial was conducted from April 18, 2018, to Sept 21, 2020; 468 participants were assessed for eligibility. Of these, 415 participants were randomly assigned to eight groups (n=53 in groups 1, 5, and 6; n=52 in groups 2 and 8; n=51 in groups 3 and 7; and n=50 in group 4) and 373 were evaluable for immunogenicity. On day 57, serum neutralising antibody geometric mean titres were 2057·0 (95% CI 1584·8-2670·0) in group 1, 1116·2 (852·5-1461·4; p=0·0015 vs group 1 used as a reference) in group 2, 1465·3 (1119·1-1918·4; p=0·076) in group 3, 2023·8 (1550·5-2641·7; p=0·93) in group 4, 920·1 (710·9-1190·9; p<0·0001) in group 5, 1206·9 (932·4-1562·2; p=0·0045) in group 6, 1562·8 (1204·1-2028·3; p=0·14) in group 7, and 1712·5 (1330·0-2205·0; p=0·32) in group 8. In group 4, a booster dose increased serum neutralising antibody geometric mean titres from 215·7 (95% CI 160·9-289·1) on day 547 to 10 941·1 (7378·0-16 225·1) on day 575. Durability of the immune response (evaluated in groups 1, 4, and 8) was shown up to 2 years. The most common solicited adverse event was pain at the injection site, reported in 12 (23%) of 53 participants who received the unadjuvanted vaccine (group 1) and 111 (31%) of 356 who received the adjuvanted vaccine. No vaccine-related serious adverse events were reported. PXVX0317 was well tolerated and induced a robust and durable serum neutralising antibody immune response against CHIKV up to 2 years. A single 40 μg injection of adjuvanted PXVX0317 is being further investigated in phase 3 clinical trials (NCT05072080 and NCT05349617). Emergent BioSolutions.

Immunogenicity and safety of NVSI-06-07 as a heterologous booster after priming with BBIBP-CorV: a phase 2 trial

The increased coronavirus disease 2019 (COVID-19) breakthrough cases pose the need of booster vaccination. We conducted a randomised, double-blinded, controlled, phase 2 trial to assess the immunogenicity and safety of the heterologous prime-boost vaccination with an inactivated COVID-19 vaccine (BBIBP-CorV) followed by a recombinant protein-based vaccine (NVSI-06-07), using homologous boost with BBIBP-CorV as control. Three groups of healthy adults (600 individuals per group) who had completed two-dose BBIBP-CorV vaccinations 1–3 months, 4–6 months and ≥6 months earlier, respectively, were randomly assigned in a 1:1 ratio to receive either NVSI-06-07 or BBIBP-CorV boost. Immunogenicity assays showed that in NVSI-06-07 groups, neutralizing antibody geometric mean titers (GMTs) against the prototype SARS-CoV-2 increased by 21.01–63.85 folds on day 28 after vaccination, whereas only 4.20–16.78 folds of increases were observed in control groups. For Omicron variant, the neutralizing antibody GMT elicited by homologous boost was 37.91 on day 14, however, a significantly higher neutralizing GMT of 292.53 was induced by heterologous booster. Similar results were obtained for other SARS-CoV-2 variants of concerns (VOCs), including Alpha, Beta and Delta. Both heterologous and homologous boosters have a good safety profile. Local and systemic adverse reactions were absent, mild or moderate in most participants, and the overall safety was quite similar between two booster schemes. Our findings indicated that NVSI-06-07 is safe and immunogenic as a heterologous booster in BBIBP-CorV recipients and was immunogenically superior to the homologous booster against not only SARS-CoV-2 prototype strain but also VOCs, including Omicron.

Heterologous ChAdOx1 and Bnt162b2 vaccination induces strong neutralizing antibody responses against SARS-CoV-2 including delta variant with tolerable reactogenicity

ObjectivesWe assessed humoral responses and reactogenicity following the heterologous vaccination compared to the homologous vaccination groups. MethodsWe enrolled healthcare workers (HCWs) who were either vaccinated with ChAdOx1 followed by BNT162b2 (heterologous group) or 2 doses of ChAdOx1 (ChAdOx1 group) or BNT162b2 (BNT162b2 group). Immunogenicity was assessed by measuring antibody titers against receptor-binding domain (RBD) of SARS-CoV-2 spike protein in all participants and neutralizing antibody titer in 100 participants per group. Reactogenicity was evaluated by a questionnaire-based survey. ResultsWe enrolled 499 HCWs (ChAdOx1, n = 199; BNT162b2, n = 200; heterologous ChAdOx1/BNT162b2, n = 100). The geometric mean titer of anti–receptor-binding domain antibody at 14 days after the booster dose was significantly higher in the heterologous group (11 780.55 binding antibody unit (BAU)/mL [95% CI, 10 891.52–12 742.14]) than in the ChAdOx1 (1561.51 [95% CI, 1415.03–1723.15]) or BNT162b2 (2895.90 [95% CI, 2664.01–3147.98]) groups (both p < 0.001). The neutralizing antibody titer of the heterologous group (geometric mean ND50, 2367.74 [95% CI, 1970.03–2845.74]) was comparable to that of the BNT162b2 group (2118.63 [95% CI, 1755.88–2556.32]; p > 0.05) but higher than that of the ChAdOx1 group (391.77 [95% CI, 326.16–470.59]; p < 0.001). Compared with those against wild-type SARS-CoV-2, the geometric mean neutralizing antibody titers against the Delta variant at 14 days after the boosting were reduced by 3.0-fold in the heterologous group (geometric mean ND50, 872.01 [95% CI, 685.33–1109.54]), 4.0-fold in the BNT162b2 group (337.93 [95% CI, 262.78–434.57]), and 3.2-fold in the ChAdOx1 group (206.61 [95% CI, 144.05–296.34]). The local or systemic reactogenicity after the booster dose in the heterologous group was higher than that of the ChAdOx1 group but comparable to that of the BNT162b2 group. DiscussionHeterologous ChAdOx1 followed by BNT162b2 vaccination with a 12-week interval induced a robust humoral immune response against SARS-CoV-2, including the Delta variant, that was comparable to the homologous BNT162b2 vaccination and stronger than the homologous ChAdOx1 vaccination, with a tolerable reactogenicity profile.

Effect of BTN162b2 and CoronaVac boosters on humoral and cellular immunity of individuals previously fully vaccinated with CoronaVac against SARS-CoV-2: A longitudinal study.

BackgroundIt is essential to know about immune response levels after booster doses of the two different types of vaccines, mRNA, and the inactivated, currently used against COVID‐19. For this purpose, we aimed to determine the effects of BNT162b2 (BNT) and CoronaVac (CV) boosters on the humoral and cellular immunity of individuals who had two doses of CV vaccination.MethodsThe study was conducted in three centers (Koc University Hospital, Istanbul University Cerrahpasa Hospital, and Istanbul University, Istanbul Medical School Hospital) in Istanbul, Turkey. Individuals who had been previously immunized with two doses of CV and no history of COVID‐19 were included. The baseline blood samples were collected 3–5 months after the second dose of CV. Follow‐up blood samples were taken 1 and 3 months after administration of third doses of CV, or one dose of BNT boosters. Neutralizing antibody titers were measured by plaque reduction assay. The CD4+ T cell, CD8+ T cell, effector CD4+CD38+CD69+ T cell, and effector CD8+CD38+CD69+ T cell ratios were determined by flow cytometry. The intracellular IFN‐γ and IL‐2 responses were measured by ELISpot assay.ResultsWe found a 3.38‐fold increase in neutralizing antibody geometric mean titers (NA GMT, 78.69) 1 month after BNT booster and maintained at the third month (NA GMT, 80). Nevertheless, in the CV booster group, significantly lower NA GMT than BNT after 1 month and 3 months were observed (21.44 and 28.44, respectively) (p < .001). In the ELISpot assay, IL‐2 levels after BNT were higher than baseline and CV booster (p < .001) while IFN‐γ levels were significantly higher than baseline (p < .001). The CD8+CD38+CD69+ and CD4+CD38+CD69+ T cells were stimulated predominantly in the third month of the BNT boosters.ConclusionThe neutralizing antibody levels after 3 months of the BNT booster were higher than the antibody levels after CV in fully vaccinated individuals. On the contrary, ratio of the effector T cells increased along with greater IFN‐γ activation after BNT booster. By considering the waning immunity, we suggest a new booster dose with BNT for the countries that already had two doses of primary CV regimens.

Safety and immunogenicity of 3 formulations of a Sabin inactivated poliovirus vaccine produced on the PER.C6® cell line: A phase 2, double-blind, randomized, controlled study in infants vaccinated at 6, 10 and 14 weeks of age

ABSTRACT An inactivated poliovirus vaccine candidate using Sabin strains (sIPV) grown on the PER.C6® cell line was assessed in infants after demonstrated immunogenicity and safety in adults. The study recruited 300 infants who were randomized (1:1:1:1) to receive one of 3 dose levels of sIPV or a conventional IPV based on Salk strains (cIPV). Poliovirus-neutralizing antibodies were measured before the first dose and 28 days after the third dose. Reactogenicity was assessed for 7 days and unsolicited adverse events (AEs) for 28 days after each vaccination. Serious AEs (SAEs) were recorded throughout the study. Solicited AEs were mostly mild to moderate. None of the SAEs reported in the study were judged vaccine related, including one fatal SAE due to aspiration of vomitus that occurred 26 days after the third dose of low-dose sIPV. After 3 sIPV vaccinations and across all dose levels, seroconversion (SC) rates were at least 92% against Sabin poliovirus types and at least 80% against Salk types, with a dose-response in neutralizing antibody geometric mean titers (GMTs) observed across the 3 sIPV groups. Compared to cIPV, the 3 sIPV groups displayed similar or higher SC rates and GMTs against the 3 Sabin types but showed a lower response against Salk types 1 and 2; this was most visible for Salk type 1. While the PER.C6® cell line-based sIPV showed an acceptable safety profile and immunogenicity in infants, lower seroprotection against type 1 warrants optimization of dose level and additional clinical evaluation.

Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study

Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study

Safety and immunogenicity of CpG 1018 and aluminium hydroxide-adjuvanted SARS-CoV-2 S-2P protein vaccine MVC-COV1901: interim results of a large-scale, double-blind, randomised, placebo-controlled phase 2 trial in Taiwan

BackgroundMVC-COV1901, a recombinant protein vaccine containing pre-fusion-stabilised spike protein S-2P adjuvanted with CpG 1018 and aluminium hydroxide, has been shown to be well tolerated with a good safety profile in healthy adults aged 20–49 years in a phase 1 trial, and provided a good cellular and humoral immune responses. We present the interim safety, tolerability, and immunogenicity results of a phase 2 clinical trial of the MVC-COV1901 vaccine in Taiwan.MethodsThis is a large-scale, double-blind, randomised, placebo-controlled phase 2 trial done at ten medical centres and one regional hospital in Taiwan. Individuals aged 20 years or older who were generally healthy or had stable pre-existing medical conditions were eligible for enrolment. Exclusion criteria included (but were not limited to) travel overseas within 14 days of screening, intention to travel overseas within 6 months of the screening visit, and the absence of prespecified medical conditions, including immunosuppressive illness, a history of autoimmune disease, malignancy with risk to recur, a bleeding disorder, uncontrolled HIV infection, uncontrolled hepatitis B and C virus infections, SARS-CoV-1 or SARS-CoV-2 infections, an allergy to any vaccine, or a serious medical condition that could interfere with the study. Study participants were randomly assigned (6:1) to receive two doses of either MVC-COV1901 or placebo, administered via intramuscular injection on day 1 and day 29. MVC-COV1901 contained 15 μg of S-2P protein adjuvanted with 750 μg CpG 1018 and 375 μg aluminium hydroxide in a 0·5 mL aqueous solution, and the placebo contained the same volume of saline. Randomisation was done centrally by use of an interactive web response system, stratified by age (≥20 to <65 years and ≥65 years). Participants and investigators were masked to group assignment. The primary outcomes were to evaluate the safety, tolerability, and immunogenicity of MVC-COV1901 from day 1 (the day of the first dose) to day 57 (28 days after the second dose). Safety was assessed in all participants who received at least one dose. Immunogenicity was assessed by measuring geometric mean titres (GMTs) and seroconversion rates of neutralising antibody and antigen-specific IgG in the per-protocol population. This study is registered with ClinicalTrials.gov, NCT04695652.FindingsOf 4173 individuals screened between Dec 30, 2020, and April 2, 2021, 3854 were enrolled and randomly assigned: 3304 to the MVC-COV1901 group and 550 to the placebo group. A total of 3844 participants (3295 in the MVC-COV1901 group and 549 in the placebo group) were included in the safety analysis set, and 1053 participants (903 and 150) had received both doses and were included in the per-protocol immunogenicity analysis set. From the start of this phase 2 trial to the time of interim analysis, no vaccine-related serious adverse events were recorded. The most common solicited adverse events in all study participants were pain at the injection site (2346 [71·2%] of 3295 in the MVC-COV1901 group and 128 [23·3%] of 549 in the placebo group), and malaise or fatigue (1186 [36·0%] and 163 [29·7%]). Fever was rarely reported (23 [0·7%] and two [0·4%]). At 28 days after the second dose of MVC-COV1901, the wild-type SARS-CoV-2 neutralising antibody GMT was 662·3 (95% CI 628·7–697·8; 408·5 IU/mL), the GMT ratio (geometric mean fold increase in titres at day 57 vs baseline) was 163·2 (155·0–171·9), and the seroconversion rate was 99·8% (95% CI 99·2–100·0).InterpretationMVC-COV1901 has a good safety profile and elicits promising immunogenicity responses. These data support MVC-COV1901 to enter phase 3 efficacy trials.FundingMedigen Vaccine Biologics and Taiwan Centres for Disease Control, Ministry of Health and Welfare.