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Background: Although mRNA SARS-CoV-2 vaccines have received emergencyuse- authorization for infants age 6 months and older, vaccine uptake is slow, stressing that questions of safety and durability of vaccine efficacy remain prominent. Method(s): Infant rhesus macaques (RMs) (n=8/group) at 2 months of age, comparable to human toddler age, were immunized intramuscularly at weeks 0 and 4 with 30mug stabilized prefusion SARS-CoV-2 S-2P spike (S) protein (Washington strain) encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or 15mug S protein mixed with 3M-052 in stable emulsion (Protein). At 1 year, vaccinated and age-matched unvaccinated RM (n=8) were challenged intranasally (106pfu) and intratracheally (2x106pfu) with B.1.617.2. Lung radiographs and pathology were blindly assessed, viral N gene RNA (vRNA) copies were measured by qPCR in pharyngeal swabs and lung, and neutralizing antibody and peripheral blood T cell responses were measured. Result(s): At 1 year, D614G-specific neutralizing antibody (nAb) titers were still detectable in the Protein (ID50=755;range: 359-1,949) and mRNA-LNP groups (ID50=73;range: 41-240). Both vaccines also induced cross-neutralizing antibodies to B.1.617.2. Peripheral blood CD4+ T cell responses to the ancestral spike protein at week 52 did not differ between the groups. However, median CD8+ T cell responses were higher (p=0.002, Mann Whitney) in the mRNA-LNP group (2.8%;range: 0.9%-7.1%) compared to the Protein group (0.8%;range: 0.1%-1.6%). Control RMs had significantly higher median vRNA copies/ml (1.4+/-2.7x108) in day 4 pharyngeal swabs compared to Protein (3.8+/-6.8x103) or mRNA-LNP (4.4+/-9.7x105) vaccinated RMs. Severe lung pathology was observed in 7 of 8 controls compared to 1 of 8 or 0 of 8 RMs in the mRNA-LNP or Protein group respectively. Protection against lung inflammation was associated with nAb titers (r=-0.592, p=0.003) (Figure 1). Conclusion(s): These results demonstrate that despite lower vaccine doses compared to adults, both protein and mRNA vaccines were safe, induced durable immune responses and provided comparable protective efficacy against infection with a heterologous SARS-CoV-2 variant in infants, implying that early life vaccination of human infants may lead to durable immunity. Neutralizing ID50 antibody titers are a correlate of protection in infant RMs challenged with SARS-CoV-2.
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Background. Vaccination strategies that provide enhanced immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are needed. We evaluated the safety and immunogenicity of a bivalent omicron containing vaccine, mRNA-1273.214 (50 mug), administered as a second booster dose in adult participants. Methods. In this ongoing phase 2/3 trial, 50 mug of the bivalent vaccine mRNA-1273.214 (25 mug each ancestral Wuhan-Hu-1 and omicron BA.1 spike mRNAs) or 50 mug of the authorized mRNA-1273 were administered as second boosters in adults who previously received a 2 dose (100 mug) primary series and a first booster (50 mug) dose of mRNA-1273 (>= 3 months prior). Primary objectives were safety and reactogenicity and immunogenicity 28 days post-booster dose. Results. In participants with no prior SARS-CoV-2 infection who received booster doses of mRNA-1273.214 (n=334) or mRNA-1273 (n=260), neutralizing antibody (nAb) geometric mean titers (GMTs [95% confidence interval (CI)]) against omicron BA.1 were 2372.4 (2070.6-2718.2) and 1473.5 (1270.8-1708.4), respectively. The model-based GMT ratio (GMR [97.5% CI]) of mRNA-1273.214 compared to mRNA-1273 was 1.75 (1.49-2.04), meeting the pre-specified superiority criterion against omicron BA.1. The pre-specified criterion for non-inferiority against the ancestral SARS-CoV-2 strain was also met. Additionally, mRNA-1273.214 elicited higher GMTs (727.4 [632.8-836.1]) than mRNA-1273 (492.1 [431.1-561.9]) against omicron subvariants BA.4/BA.5 [GMR (95% CI) 1.69 [1.51-1.90])]. Binding antibody responses against alpha, beta, gamma, delta, and omicron were numerically higher in the mRNA-1273.214 group compared to mRNA-1273. mRNA-1273.214 GMTs were consistently higher across age (18-< 65 and >= 65 years) and pre-booster SARS-CoV-2 infection subgroups (Figure). Safety and reactogenicity were similar for both vaccine groups. Conclusion. The bivalent omicron containing mRNA-1273.214 elicited superior nAb responses against omicron 28 days post-immunization compared to mRNA-1273 regardless of age and prior SARS-CoV-2 infection;no new safety concerns were identified. (Figure Presented).
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[Figure: see text].
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Background: SARS-CoV-2 has claimed over a million lives and remains a global threat. Understanding immune responses to infection and developing validated laboratory assays to measure them is critical to the rapid development, assessment and implementation of effective interventions. Our development of a validated pseudovirus neutralization assay and characterization of neutralizing antibody (nAb) profiles in a diverse post-SARS-CoV-2 cohort can inform preventative and therapeutic efforts, including vaccine and monoclonal antibody development and deployment. Methods:This analysis comprises an observational cohort of n=330 adults in the US (n=168) and Peru (n=162), convalescing from SARS-CoV-2 infection and stratified by age, asymptomatic or symptomatic infection, and hospitalization. NAb titers are measured in serum by SARS-CoV-2.D614G Spike-pseudotyped virus infection of 293T/ACE2 cells. Multiple linear regression is applied to define associations between nAb titers and demographic variables, disease severity and duration, and co-morbidities within and across US and Peruvian cohorts over time. Results: The mean age is 48 years;49% were assigned female sex at birth, 51% male;54% are Latinx;50% identified as Other race, 34% White, 11% Black, 4%Asian. The mean days from SARS-CoV-2 diagnosis to enrollment was 52. NAb titers were higher in participants with a history of severe illness (p<0.001) and peaked 28-42 days post-diagnosis. ID50 (ID80) nAb titers >20 were detected at enrollment in 66% (46%) of asymptomatic, 86% (74%) of symptomatic and 95% (92%) of hospitalized individuals. Median ID50 (ID80) titers at enrollment among asymptomatic, symptomatic and hospitalized individuals were 107 (10), 482 (59) and 1,953 (366), respectively. Two months post-enrollment, median ID50 (ID80) titers among asymptomatic, symptomatic and hospitalized individuals declined to 30 (10), 130 (16) and 564 (103), respectively. Diabetes (p=0.011), age >55yo (p<0.001), male sex (p=0.003) and BMI ≥30 (p=0.021) were associated with higher ID80 titers. Hypertension was associated with lower ID50 titers (p=0.005). Conclusion: NAb titers after SARS-CoV-2 infection correlate with illness severity and underlying co-morbidities, and peak approximately one month postdiagnosis. Large, diverse, well-characterized cohorts of convalescent individuals facilitate development of standardized laboratory methods and reagents to measure immune responses and provide standardized values to benchmark SARS-CoV-2 vaccine-elicited responses.
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Background: Maternal antibodies are important for infant immunity, and understanding the maternal and umbilical cord antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will be important for neonatal management and maternal vaccination strategies. Methods: The dynamics of maternal/ umbilical cord antibody responses to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were analyzed in 81 samples from 69 pregnant women studied between April 2020 and January 2021. Binding IgG, IgA and IgM antibodies to RBD were measured by enzyme-linked immunosorbent assay (ELISA) in both maternal and cord blood. Neutralization was assessed using codon-optimized full-length G614 Spike-pseudotyped virus (VRC7480.D614G). Results: Among the 69 pregnant women, 57 were either symptomatic or asymptomatic infection and 17 samples were taken during the time of delivery resulting in paired maternal/umbilical cord blood samples. Among the maternal samples tested, the RBD specific IgG were detected in 93%, IgA were detected in 67% and IgM were detected in 79%. The RBD-specific IgG was detected in 12 of 17 (70%) umbilical cord blood, but IgM and IgA were not detected in the cord blood samples. The IgG antibody concentration were significantly (P < 0.004) lower (7 fold) in the cord blood when compared to maternal blood. However, the cord blood IgG titers were positively correlated with maternal IgG titers (r = 0.59;P < 0.003). In line with that, the circulating T-follicular helper cells (p<0.0001) and signaling lymphocytic activation molecule family 1(SLAMF1) were lower (p<0.004) in cord relative to maternal blood. Among the samples tested, 71.4% had neutralization titers. Interestingly, the neutralization capacity of plasma from cord blood was negative when compared to maternal blood (mean titer of 20 vs 2128 respectively), suggesting that cord blood does not have capacity to neutralize the SARS-CoV-2 virus. Conclusion: In this cohort study, maternal IgG, IgA and IgM antibodies to RBD of SARS-CoV-2 were seen in maternal samples. However the cord blood IgG levels were significantly lower and did not show positive titers for IgA and IgM. Although both maternal and cord blood has RBD binding antibodies, there is no neutralization seen in any of the cord blood tested compared to respective maternal blood. Our findings demonstrate that maternally-derived SARS-CoV-2 specific antibodies lack neutralization potential to provide neonatal protection from COVID-19. (Figure Presented).
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Background: SARS-CoV-2 vaccines have shown promising efficacy in human adult trials, but immunogenicity and efficacy studies in the pediatric population are lagging behind. Here we evaluated the immunogenicity of two prefusion stabilized Spike protein (S-2P) vaccine platforms in infant Rhesus Macaques (RM): an adjuvanted S-P2 subunit and mRNA vaccine. Methods: Infant RMs (2.5 months-old) were immunized intramuscularly at weeks (wks) 0 & 4 with 15 μg S-P2 adjuvanted with the toll-like receptor 7/8 agonist 3M-052 in stable emulsion (n=8), or 30 μg of S-P2 mRNA in lipid nanoparticles (mRNA-LNP, Moderna) (n=8). Blood was collected at wks 0, 4, 6, 8, & 14. Plasma (Spike[S]) and salivary (receptor binding domain [RBD]) IgG responses were measured by ELISA and epitope specificity by multiparameter bead array. Antibody function was assessed by an ACE2 blocking assay and neutralization by pseudovirus (PSVA) and whole virus neutralization assays, both with D614G. Flow cytometry was applied to measure S-specific memory B cells using fluorochrome-conjugated recombinant S, and S-specific IL-2, IL-17, TNF-α, or IFN-γ producing T cells after stimulation with overlapping peptides of full-length S. Results: No adverse effects were observed with either vaccine. Plasma S-specific IgG responses were induced by both vaccines at wk 4, increased after the second dose, and persisted through wk 14 (Fig 1A). All S regions were targeted by plasma IgG (Fig 1B), and RBD-specific IgG was also detected in saliva. Serum antibodies achieved >95% ACE2 blocking by wk 6 (1:10 dilution), remaining >90% at wk 14. Geometric mean ID50 titers of neutralizing antibodies in the PSVA exceeded 10[3] from wk 6 through wk 14 (Fig 1C) and strongly correlated with whole virion neutralization (p<0.0001). In the protein vaccine group, S-specific CD27+ memory B cells peaked at 3.1% (mean) of total memory B cells;and S-specific CD4+ T cell responses were dominated by IL-17 and IFN-γ Mean S-specific CD27+ B cells peaked at 0.9% total memory B cells in mRNA vaccinees and S-specific CD4+ T cells produced IL-2, IFN-γ, IL-17, or TNF-α. Conclusion: The S-2P-3M-052-SE and mRNA-LNP vaccines were well-tolerated and highly immunogenic in infant Rhesus Macaques, with persistent IgG binding and neutralization responses that are comparable to those reported for adult RMs and humans. Our results provide proof-of-concept that a pediatric SARS-CoV-2 vaccine could induce long term protection against SARS-CoV-2.