ABSTRACT
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.
ABSTRACT
Background:: Most research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy has been on acute infections with limited data on the effect of distant infection. Aim:: We examined placental pathology and neonatal outcomes in distant SARS-CoV-2 infection earlier in pregnancy compared to acute infections late in pregnancy/at birth and to non-SARS-CoV-2 infected patients with other placental pathologies/clinical presentations. Methods:: Placentas birthed to unvaccinated patients with SARS-CoV-2 reverse transcription–polymerase chain reaction (RT-PCR) testing and serology testing results from time of delivery were included in this study. A total of 514 singleton placentas between April 18, 2020, and July 26, 2021, were included: 77 acute SARS-CoV-2 infection (RT-PCR positive and serology negative);222 distant SARS-CoV-2 infection (RT-PCR negative but serology IgG-positive);and 215 non-SARS-Cov-2 infected (RT-PCR negative, serology negative, and history negative) with other placental pathologies: preeclampsia/hypertension, intrauterine growth restriction (IUGR), diabetes, chorioamnionitis, and meconium. Placental pathology findings, Apgar scores, and neonatal birth weights were compared. Results:: Placentas from the acute group had significantly more villous agglutination (10.4%, P = 0.015) and eosinophilic T-cell vasculitis (5.2%, P = 0.004) compared to placentas from the distant group (2.7% and 0%) and non-SARS-CoV-2 placentas (1.9% and 0.9%). One acute case showed SARS-CoV-2 placentitis and resulted in preterm delivery at 25 weeks. Both the preeclampsia/hypertension and the IUGR groups showed significantly more maternal vascular malperfusion findings compared to the acute (6.5%, 6.5% and 1.3%) and distant (7.7%, 7.7%, and 3.2%) groups. Fetal vascular malperfusion findings such as thrombosis of fetal vessels (17.4% P = 0.042) and intramural fibrin deposition (21.7% P = 0.026) were significantly higher in the IUGR group compared to acute (7.8%;2.6%) and distant (3.6%;8.1%) infection. Many neonates born to patients infected with SARS-CoV-2 had birth weights outside of 95% confidence range of observed birth weights. There was no association of Apgar scores with infection status or placental pathology. Conclusion:: Acute and distant SARS-CoV-2 infections present differing placental pathology. Relevance for Patients:: SARS-CoV-2 infection during pregnancy has demonstrable effects on the placenta with potential significant impacts for maternal and fetal health. Prevention of maternal SARS-CoV-2 infection, primarily through vaccination, remains the best mitigation strategy to prevent sequelae of maternal SARS-CoV-2 infection.
ABSTRACT
Background: The low susceptibility of children to severe illness with SARS-CoV- 2 infection could be related to distinct virus-host interactions. Some studies indicate that SARS-CoV-2 infected adults with mild symptoms rapidly lose their antibody responses, but the kinetics of the antibody response in children have been less studied. To evaluate the antibody response of SARS CoV-2 antibodies in infected children, we used samples from the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study, a community-based prospective cohort study of children and adolescents with SARS-CoV-2 infection or exposure. Methods: Samples from 71 SARS-CoV-2 infected children (median age: 9.7 years, IQR 4-16) collected at enrollment (M0), 2 and 4 months after exposure (M2, M4) were analyzed. A Luminex-based multiplex binding assay was used to measure Ig isotype (IgG, IgM, IgA) and IgG subclass (IgG1, IgG3) against 7 SARS-CoV-2 epitopes: whole spike (S), subunit 1 (S1), S2, receptor binding domain (RBD), N-terminal domain (NTD), nucleocapsid (NC) and membrane (M). The ability of antibodies to block viral interaction with the human receptor ACE2 was evaluated by an ELISA-based assay, and neutralization was assessed in a pseudovirus assay. Results: At time of enrollment (median of 5 days after infection), all participants had detectable levels of IgM and IgA against at least one of the tested SARS-CoV-2 antigens, and 91% had detectable IgG levels. IgM and IgA levels declined with time, although all children still had detectable levels of anti-S IgM and IgA at M4. In contrast, IgG binding to all viral regions increased significantly at M2 and, at M4, most children maintained robust IgG response. IgG1 and IgG3 antibodies were detected against most antigens. ACE2 blocking increased at M2 as compared to M0, and at M2 the percent blocking was higher in younger children than in older children (Fig 1). Similarly, younger children had higher levels of anti-RBD IgG at M2, whereas older children showed higher levels of anti-RBD IgM. We found no differences in antibody profiles between asymptomatic and symptomatic children. Preliminary analysis in 4 children indicated that neutralizing antibody responses were still detectable at M4. Conclusion: SARS CoV-2 infected children develop robust antibody responses that are still detectable 4 months after infection. This suggests that children could respond well to SARS CoV-2 vaccination and highlights the need to test candidate vaccines in pediatric populations.
ABSTRACT
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.