BACKGROUND:Impact of prior inactivated poliovirus vaccine (IPV) doses on nasal and pharyngeal viral replication following subsequent poliovirus exposure remains unclear. Circulating vaccine-derived poliovirus detection in IPV-only countries necessitates better understanding of IPV's role in inducing nasal and pharyngeal mucosal immunity. METHODS:This multicenter, randomized, open-label, parallel-group trial (9 November 2023-25 August 2024; ClinicalTrials.gov identifier: NCT05677256) was conducted in Bangladesh in 500 polio vaccine-naïve infants aged 6-8 weeks. Two infant cohorts (vaccinated with 3 doses of either IPV or bivalent oral poliovirus vaccine [bOPV]) were challenged at 18-20 weeks with novel OPV type 2 (nOPV2). Pharyngeal and fecal viral shedding, and nasal, intestinal, and serum immune responses were measured post-nOPV2-challenge. RESULTS:Poliovirus type 2 (PV2) pharyngeal shedding was minimal post-challenge (1.7% of IPV-vaccinated and 2.6% of bOPV-vaccinated infants). Nasal PV2-specific neutralizing antibody titers were higher in the IPV group post-nOPV2-challenge (day 14; geometric mean titers [GMT]: IPV, 7.5 [95% CI: 5.1-11.1] vs bOPV, 0.6 [95% CI: 0.3-1.2]). Stool PV2-specific neutralization titers were comparable at day 14 (GMT: IPV, 124.0 [95% CI: 54.7-281.0] vs bOPV, 127.3 [95% CI: 74.0-218.9]). Serum PV2 neutralizing antibody titers were consistently higher in IPV group, peaking at day 28 (GMT: IPV, 4347.4 [95% CI: 2378.2-7947.2] vs bOPV, 259.9 [95% CI: 115.5-584.9]). CONCLUSIONS:nOPV2 pharyngeal shedding was low following IPV or bOPV vaccination, whereas IPV induced higher nasal and serum, and comparable intestinal PV2-specific immunity, suggesting a potential role for IPV in poliovirus outbreak response in IPV-only settings.

The portfolio of next generation COVID-19 vaccines would benefit from candidates that induce durable systemic and mucosal immune responses that would lessen person-to-person transmission. We constructed an intranasal (IN) replication-competent adenovirus type 4 recombinant platform to express SARS-CoV-2 Spike variants (Ad4-S) and assessed immunogenicity and efficacy in the Syrian hamster model. Although both IN Ad4-S and intramuscular (IM) vaccines (Ad26.CoV2.S and mRNA-1273) induced serum binding antibodies, only Ad4-S induced a robust mucosal response in the nasal cavity. IN Ad4-S vaccination induced serum neutralizing titers equivalent to or greater than IM vaccination but more durable up to 6 months. Upon challenge, IN immunization also resulted in less weight loss, greater breadth and durability of restriction of viral replication, and less lung pathology than IM immunization up to 268 days after immunization. These data support the potential of the IN Ad4 vaccine platform to reduce transmission of SARS-CoV-2 and other respiratory viruses with pandemic potential.

Background:People with cystic fibrosis (pwCF) are at increased risk of severe disease following respiratory viral infections including influenza and respiratory syncytial virus, and were therefore given priority for COVID-19 vaccination. Retrospective epidemiological data have revealed a lower incidence of SARS-CoV-2 infection and a reduced fatality rate among pwCF than in the general population, possibly from the stringent infection control measures and early adoption of protective behaviors. Despite several reports of adequate binding and neutralizing titers after vaccination, the molecular features of vaccine-elicited serum antibody repertoires in pwCF remain unknown. Methods:We performed high-resolution proteomic analysis of serum IgG, combined with next-generation sequencing of B cells, to quantitatively profile Spike (S)-reactive serological repertoires from nine infection-naïve pwCF after two doses of COVID-19 mRNA vaccine. We recombinantly expressed 20 IgG clonotypes from 6 pwCF as monoclonal antibodies (mAbs) and measured their binding and neutralization against vaccine-strain and variant viruses. Results:All donors mounted strong binding and neutralizing titers to vaccine-strain virus. Ig-Seq revealed diverse serum repertoires in all vaccinees, with antibodies targeting the receptor-binding domain (RBD) comprising 64% of each circulating repertoire by abundance. Several serum IgG clonotypes identified across our cohort shared identical or similar IGHV and CDRH3 amino acid sequences with serum IgG from other pwCF or S-reactive mAbs isolated from non-CF individuals. These 'convergent' antibodies made up 14.6% of the anti-S repertoires in our cohort, reaching 24.8% in one pwCF. Convergent antibodies tended to be RBD-reactive and enriched in specific IGHV ; surprisingly, a higher abundance of convergent antibodies in serum correlated with a lower breadth of serum neutralization. All 20 mAbs bound Wuhan S with high affinity (EC 50 < 10 nM), and only RBD-reactive mAbs conferred neutralization to vaccine or variant pseudovirus. While most mAbs bound both the B.1.617.2 (Delta, 17/20) and B.1.1.529 (Omicron, 12/20) strains, convergent mAbs were less likely to bind either variant. Conclusions:Post-vaccine serum IgG repertoires in pwCF are dominated by RBD-focused, high-affinity antibodies and include a substantial convergent component shared with non-CF vaccinees. These findings demonstrate that pwCF mount antibody responses comparable to the general population, and a large group of convergent antibodies may contribute to strain-specific rather than cross-variant immunity.

Abstract Background Mucosal immunity is critical for preventing poliovirus transmission. Despite evidence that infant immunisation protects against poliovirus infection into adulthood, the duration of vaccine-induced intestinal antibody responses remains poorly characterised. Methods We evaluated poliovirus type-specific neutralising activity and immunoglobulin levels in stool and serum from children in Tanzania who completed routine poliovirus vaccine series (bivalent oral polio vaccine at birth, 6, 10, and 14-weeks, and inactivated polio vaccine at 14-weeks). The study included a longitudinal cohort with four visits over 6 months and a cross-sectional sample of children recruited 1 to 108-months after vaccine series completion. Potential modification by nutritional factors, gastrointestinal infections, and environmental enteropathy was explored. Results Among 103 longitudinal and 246 cross-sectional participants enrolled, 33% and 18% had positive poliovirus type-1 (PV1) stool neutralisation, and 66% and 56% had positive poliovirus type-3 (PV3) neutralisation 1 month after vaccination. All were seropositive for PV1 and PV3 across timepoints. Infants followed longitudinally who were stool neutralisation-positive at enrolment had no boost in neutralisation after vaccination, while those stool neutralisation-negative at enrolment experienced a weak boost at 1 month. Stool neutralisation half-life among longitudinal cohort infants was 3.4 months [95% CI 2.6-5.0] for PV1 and 1.7 months [1.4-2.3] for PV3. Moderate evidence suggested concurrent viral intestinal infections were associated with lower neutralisation responses (PV1 p=0.153; PV3 p=0.052). Conclusion Intestinal antibody responses to poliovirus vaccination were short-lived. The impact of waning intestinal antibodies on transmission risk remains unclear and research is needed to identify vaccination strategies that induce durable mucosal immunity.

BACKGROUND:Approximately 1.5 billion doses of novel oral polio vaccine type 2 (nOPV2) have been administered in response to circulating vaccine-derived poliovirus type 2 (cVDPV2) outbreaks since 2021. Although infants are eligible to receive the vaccine from birth, the induction of intestinal mucosal immunity by nOPV2 in newborns has not been directly evaluated. METHODS:In a randomized, placebo-controlled, phase 2 clinical trial in Bangladesh (2020-2021), 215 healthy newborns received 2 doses of either nOPV2 (n = 110) or placebo (sucrose; n = 105), at birth (0-3 days) and 4 weeks later. Intestinal mucosal antibody responses were assessed by measuring poliovirus type 2 (PV2)-specific neutralizing activity and immunoglobulin (Ig)A levels in stool collected biweekly from birth to 8-weeks. RESULTS:Newborns vaccinated with 2 doses of nOPV2 had strong intestinal mucosal antibody responses that differed significantly from the placebo group (P < .0001 for PV2-specific neutralization from 2 weeks onward and P ≤ .007 for PV2-specific IgA from 4 weeks onward). Positive PV2-specific neutralization in stool (titers ≥16) was detected in 51.8% (57/110) of nOPV2-vaccinated newborns at 4 weeks and 90.0% (99/110) at 8 weeks (4 weeks after the second dose). Notably, PV2-specific antibody titers following the second dose were very similar for newborns who did and did not have first dose responses (P = .67 for neutralization and P = .38 for IgA at 8 weeks). CONCLUSIONS:Vaccination with 2 doses of nOPV2 in neonates induced strong intestinal mucosal antibody responses. In cVDPV2 outbreak settings, neonatal administration of nOPV2 may be a strategy to enhance population-level intestinal mucosal immunity.

The portfolio of next-generation COVID-19 vaccines would benefit from candidates that induce durable systemic and mucosal immune responses that would lessen person-to-person transmission. We constructed an intranasal (IN) replication-competent adenovirus type 4 recombinant platform to express SARS-CoV-2 spike variants (Ad4-S) and assessed immunogenicity and efficacy in the Syrian hamster model. Although both IN Ad4-S and intramuscular (IM) vaccines (Ad26.CoV2.S and mRNA-1273) induced serum binding antibodies, only Ad4-S induced a robust nasal mucosal response. IN Ad4-S vaccination induced serum neutralizing titers equivalent to or greater than IM vaccination but more durable up to 6 months. Upon challenge, IN immunization also resulted in less weight loss, greater breadth and durability of restriction of viral replication, and less lung pathology than IM immunization up to 268 days after immunization. These data support the potential of the IN Ad4 vaccine platform to reduce the transmission of SARS-CoV-2 and other respiratory viruses with pandemic potential.

BACKGROUND:Reducing the risks of vaccine-derived polioviruses and vaccine-associated paralytic poliomyelitis motivated the development of novel types 1 and 3 oral poliovirus vaccines (nOPV1 and nOPV3, respectively), designed to have similar safety and immunogenicity and improved genetic stability (to reduce risk of reversion to neurovirulence) relative to types 1 or 3 Sabin-strain OPVs. We aimed to assess the safety and immunogenicity of nOPV1 and nOPV3 in healthy adults. METHODS:We did a first-in-human, observer-masked, multicentre, phase 1 randomised controlled trial in healthy adults at four centres in the USA. Participants were block randomised, stratified by site and according to polio vaccination history (inactivated poliovirus vaccine [IPV] only [hereafter IPV participants] or regimens including OPV [hereafter OPV participants]), and randomly assigned to receive either nOPV or homotypic Sabin-strain monovalent OPV (mOPV). IPV participants received a single dose of nOPV1 or mOPV1 (cohort 1) or nOPV3 or mOPV3 (cohort 3) and OPV participants received two doses 28 days apart of nOPV1 or mOPV1 (cohort 2) or nOPV3 or mOPV3 (cohort 4). The primary outcome was safety among vaccinated participants. Secondary outcomes included homotypic serum neutralising antibody responses measured before and 28 days after each dose in a per-protocol population, and faecal viral shedding mainly in IPV participants assessed up to 56 days following each dose among vaccinated participants. This study was registered with ClinicalTrials.gov (NCT04529538) and is complete. FINDINGS:Between May 6, 2021 and Feb 17, 2023, 377 individuals were assessed for eligibility, 226 were randomly assigned, and 205 receive at least one dose of nOPV1 (n=70), mOPV1 (n=45), nOPV3 (n=54), or mOPV3 (n=36). No serious adverse events were observed. Most adverse events were mild, severe events were rare, and solicited events were balanced across groups. Severe solicited events were predominantly fatigue, occurring in 1-4% of participants across all groups except for mOPV1 recipients in whom no such events were reported, and one case of nausea and vomiting in an mOPV1 recipient, and one case of abdominal pain in an nOPV1 recipient. Two (3%) participants in the nOPV1 groups (one reporting severe fatigue, headache, and myalgia, and one reporting abdominal pain) and one (2%) participant in the mOPV1 groups (kidney infection) reported a severe unsolicited adverse event within 28 days. Homotypic seroprotection was nearly 100% at baseline and was 100% 28 days after the first dose. Homotypic seroconversion rates after a single dose were high and similar for nOPV and mOPV (ranging from 86% to 100% for nOPV and from 86% to 93% for mOPV). Similar rates of viral shedding were observed among participants receiving nOPV or mOPV. Peak viral shedding rate detected via PCR among IPV participants was 100% on day 8 after a dose, across groups. INTERPRETATION:nOPV1 and nOPV3 were well tolerated and showed similar immunogenicity and shedding profiles to mOPV1 and mOPV3, respectively, supporting progression of these vaccine candidates to phase 2 studies. FUNDING:Bill & Melinda Gates Foundation.

Background: Reducing the risks of vaccine-derived polioviruses and vaccine-associated paralytic poliomyelitis from type 1 or 3 Sabin-strain oral poliovirus vaccines (OPVs) motivated the development of novel type 1 and 3 OPVs (nOPV1, nOPV3), designed to have similar safety and immunogenicity and improved genetic stability to reduce risk of reversion to neurovirulence. In this first-in-human trial, we assessed safety and immunogenicity of nOPV1 and nOPV3 in healthy adults. Methods: We conducted a multi-site, randomized, observer-blind, controlled trial in healthy adults in the United States. Participants were stratified according to poliovirus vaccination history (exclusive inactivated polio vaccine [IPV] or including OPV) and randomized to receive either nOPV or homotypic Sabin-strain monovalent OPV (mOPV); IPV participants received a single dose and OPV participants received two doses. The primary objective was to assess safety measured by adverse events. The secondary objectives were to assess serum neutralizing antibody responses measured before and 28 days after each dose and fecal viral shedding assessed up to 56 days post-first dose. This study was registered with ClinicalTrials.gov, [NCT04529538][1]. Findings: Between May 2021 and February 2023, 205 healthy adults were enrolled and received at least one dose: 70 nOPV1, 45 mOPV1, 56 nOPV3, and 38 mOPV3. Most events were mild, severe events were rare, and solicited events were balanced. Homotypic seroprotection was nearly 100% at baseline and was 100% after the first dose. Homotypic seroconversion rates after a single dose were high and similar for nOPV and mOPV (from 86 to 100%), with no statistically significant differences. Similar rates of viral shedding were observed among participants receiving nOPV or mOPV. Interpretation: Both nOPV1 and nOPV3 were well tolerated and demonstrated similar immunogenicity and shedding profiles to mOPV1 and mOPV3, respectively, supporting progression to phase 2 studies. nOPVs may be an important tool for achieving eradication of poliovirus. Funding: Gates Foundation. ### Competing Interest Statement ET is a full-time employee of the vaccine manufacturer, PT Bio Farma (Bandung, Indonesia). ASB is a full-time employee of the funder, Gates Foundation (Seattle, USA). All other authors declare no competing interests. Disclaimer: The findings in this article are those of the authors and do not necessarily represent the official position of the US CDC. ### Clinical Trial NCT04529538 ### Funding Statement This work was supported, in whole or in part, by the Gates Foundation [INV-007007]. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was approved by Advarrra Institutional Review Board (IRB), University of Vermont IRB, University of North Carolina Biomedical IRB, and Dartmouth-Hitchcock Health Human Research Protection Program. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data for this study will be made available to others in the scientific community upon request. Standard criteria for making data available for valid research projects will be used, following application by suitably qualified researchers. For data access, please contact the corresponding author. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04529538&atom=%2Fmedrxiv%2Fearly%2F2025%2F02%2F23%2F2025.02.21.25322566.atom

Using serum and bronchoalveolar lavage (BAL) fluid collected from 20 healthy adults (23-37 years, 55 % female) in the United States, we measured immunoglobulin (Ig) A, IgG, and neutralising activity against respiratory syncytial virus (RSV) and influenza A (H1N1) virus. RSV-binding IgA and IgG measurements in serum were positively correlated with those in BAL. For influenza A (H1N1) virus, serum and BAL IgA antibodies were positively correlated, whereas IgG antibodies did not show a significant correlation. RSV-specific and influenza A (H1N1)-specific neutralising activity did not correlate between serum and BAL samples. These results demonstrate virus-specific correlations between antibodies in the serum and BAL that may not necessarily reflect correlations in functional activity. Further work is needed to confirm our preliminary observations, and define the immune correlates of neutralising activity to these and other respiratory viruses in the lower respiratory tract.

BACKGROUND:A novel oral polio vaccine type 2 (nOPV2), which is more genetically stable (ie, lower risks of reverting to neurovirulence) than the Sabin monovalent OPV2 (mOPV2), has been deployed to interrupt circulating vaccine-derived poliovirus type 2 (PV2) outbreaks. This study compares intestinal mucosal immune responses induced by nOPV2 and mOPV2. METHODS:In this analysis, we evaluated intestinal mucosal immune responses in healthy participants of different ages (ie, infants aged 18-22 weeks, children aged 1-4 years, and adults aged 18-50 years) and vaccine backgrounds (ie, OPV2-experienced vs OPV2-naive). Participants were selected from two phase 2 trials of nOPV2, conducted in 2018-19 (infants and children, NCT03554798 [Panama]; adults, EudraCT 2018-001684-22-NCT04544787 [Belgium]), and two phase 4 historical control trials of mOPV2, conducted in 2015-16 (infants and children, NCT02521974 [Panama]; adults, EudraCT 2015-003325-33 [Belgium]). We measured PV2-specific neutralising activity and IgA concentrations in stools collected before and 14 days after vaccination. FINDINGS:We compared data from 160 participants (ie, 47 infants, 47 children, and 66 adults) in the nOPV2 trials to 188 participants (ie, 42 infants, 46 children, and 100 adults) in the mOPV2 trials. Within each age group, one dose of nOPV2 or mOPV2 induced similar intestinal PV2-specific neutralisation and IgA responses on day 14. Responses diminished with age: among the OPV2-naive participants who received nOPV2, 27 (82%) of 33 infants, 17 (61%) of 28 children, and four (25%) of 16 adults had detectable PV2-specific neutralisation on day 14. Despite having similar median log10 IgA responses (1·4 [IQR 1·0-2·2] vs 1·4 [1·1-1·7], p=0·34) and median log2 neutralisation titres (1 [IQR 1-1] vs 1 [1-1·5], p=0·89) on day 14, a smaller percentage of OPV2-experienced adults shed vaccine virus than OPV2-naive adults upon nOPV2 challenge (20% vs 82%, p<0·0001). INTERPRETATION:We found no evidence of differences in the intestinal mucosal immune responses induced by nOPV2 or Sabin mOPV2 and observed the strongest responses in infants. FUNDING:The Bill & Melinda Gates Foundation, Japan Agency for Medical Research and Development.

On 27 February 1962, Surgeon General Luther Terry announced a new vaccine development program within the National Institute of Allergy and Infectious Diseases (NIAID). Initially, the plan had three components: (1) special laboratories and facilities for development of prototype vaccines; (2) pilot lot production facilities and preliminary vaccine trial sites; and (3) larger lot production capacity and expanded human testing. Respiratory viruses were targeted as the top priority for vaccine development. Over 5 decades, this program has evolved and expanded to include multiple academic vaccine evaluation sites within the network, now labeled as the Vaccine and Treatment Evaluation Units (VTEUs). The network has evaluated many different vaccines, with many shown to be safe, effective, and licensed for recommended use. This manuscript offers a historical perspective, crafted by early investigators from currently funded VTEUs, to showcase how some of the original VTEUs—both individually and collectively—advanced vaccine science and shaped the strategies and achievements that continue to impact public health today.

Background Although polioviruses (PVs) replicate in lymphoid tissue of both the pharynx and ileum, research on polio vaccine-induced mucosal immunity has predominantly focused on intestinal neutralizing and binding antibody levels measured in stool.Methods To investigate the extent to which routine immunization with intramuscularly injected inactivated polio vaccine (IPV) may induce nasal and pharyngeal mucosal immunity, we measured PV type-specific neutralization and immunoglobulin (Ig) G, IgA, and IgM levels in nasal secretions, adenoid cell supernatants, and sera collected from 12 children, aged 2-5 years, undergoing planned adenoidectomies. All participants were routinely immunized with IPV and had no known contact with live PVs.Results PV-specific mucosal neutralization was detected in nasal and adenoid samples, mostly from children who had previously received 4 IPV doses. Across the 3 PV serotypes, both nasal (Spearman rho >= 0.87, P <= .0003 for all) and adenoid (Spearman rho >= 0.57, P <= .05 for all) neutralization titers correlated with serum neutralization titers. In this small study sample, there was insufficient evidence to determine which Ig isotype(s) was correlated with neutralization.Conclusions Our findings provide policy-relevant evidence that routine immunization with IPV may induce nasal and pharyngeal mucosal immunity. The observed correlations of nasal and pharyngeal mucosal neutralization with serum neutralization contrast with previous observations of distinct intestinal and serum responses to PV vaccines. Further research is warranted to determine which antibody isotype(s) correlate with polio vaccine-induced nasal and pharyngeal mucosal neutralizing activity and to understand the differences from intestinal mucosal immunity. This study provides policy-relevant evidence that children routinely immunized with inactivated polio vaccine in the United States and who had no known contact with a live poliovirus had detectable nasal and pharyngeal mucosal immunity to poliovirus.

Background: Fcγ-receptor (FcγR)-independent enhancement of SARS-CoV-2 infection mediated by N-terminal domain (NTD)-binding monoclonal antibodies (mAbs) has been observed in vitro, but the functional significance of these antibodies in vivo is less clear. Methods: We characterized 1,213 SARS-CoV-2 spike (S)-binding mAbs derived from COVID-19 convalescent patients for binding specificity to the SARS-CoV-2 S protein, VH germ-line usage, and affinity maturation. Infection enhancement in a vesicular stomatitis virus (VSV)-SARS-CoV-2 S pseudovirus (PV) assay was characterized in respiratory and intestinal epithelial cell lines, and against SARS-CoV-2 variants of concern (VOC). Proteomic deconvolution of the serum antibody repertoire was used to determine functional attributes of secreted NTD-binding mAbs. Results: We identified 72/1213 (5.9%) mAbs that enhanced SARS-CoV-2 infection in a PV assay. The majority (68%) of these mAbs recognized the NTD, were identified in patients with mild and severe disease, and persisted for at least 5 months post-infection. Infection enhancement by NTD-binding mAbs was not observed in intestinal and respiratory epithelial cell lines and was diminished or lost against SARS-CoV-2 VOC. Proteomic deconvolution of the serum antibody repertoire from 2 of the convalescent patients identified, for the first time, NTD-binding, infection-enhancing mAbs among the circulating immunoglobulins directly isolated from serum. Functional analysis of these mAbs demonstrated robust activation of FcγRIIIa associated with antibody binding to recombinant S proteins. Conclusions: Functionally active NTD-specific mAbs arise frequently during natural infection and can last as major serum clonotypes during convalescence. These antibodies display functional attributes that include FcγR activation, and may be selected against by mutations in NTD associated with SARS-CoV-2 VOC.

Here, the authors isolated and characterized genetic features of spike-specific monoclonal antibodies. They show how the antibodies evolve from infection to after vaccination and conclude that highly polyclonal repertoires of affinity-matured memory B cells are efficiently recalled by vaccination. Vaccination of SARS-CoV-2 convalescent individuals generates broad and potent antibody responses. Here, we isolate 459 spike-specific monoclonal antibodies (mAbs) from two individuals who were infected with the index variant of SARS-CoV-2 and later boosted with mRNA-1273. We characterize mAb genetic features by sequence assignments to the donors’ personal immunoglobulin genotypes and assess antibody neutralizing activities against index SARS-CoV-2, Beta, Delta, and Omicron variants. The mAbs used a broad range of immunoglobulin heavy chain ( IGH ) V genes in the response to all sub-determinants of the spike examined, with similar characteristics observed in both donors. IGH repertoire sequencing and B cell lineage tracing at longitudinal time points reveals extensive evolution of SARS-CoV-2 spike-binding antibodies from acute infection until vaccination five months later. These results demonstrate that highly polyclonal repertoires of affinity-matured memory B cells are efficiently recalled by vaccination, providing a basis for the potent antibody responses observed in convalescent persons following vaccination.

SARS-CoV-2 variants have continuously emerged in the face of effective vaccines. Reduced neutralization against variants raises questions as to whether other antibody functions are similarly compromised, or if they might compensate for lost neutralization activity. Here, the breadth and potency of antibody recognition and effector function is surveyed following either infection or vaccination. Considering pregnant women as a model cohort with higher risk of severe illness and death, we observe similar binding and functional breadth for healthy and immunologically vulnerable populations, but considerably greater functional antibody breadth and potency across variants associated with vaccination. In contrast, greater antibody functional activity targeting the endemic coronavirus OC43 is noted among convalescent individuals, illustrating a dichotomy in recognition between close and distant human coronavirus strains associated with exposure history. This analysis of antibody functions suggests the differential potential for antibody effector functions to contribute to protecting vaccinated and convalescent subjects as novel variants continue to evolve.

While our understanding of SARS-CoV-2 pathogenesis and antibody responses following infection and vaccination has improved tremendously since the outbreak in 2019, the sequence identities and relative abundances of the individual constituent antibody molecules in circulation remain understudied. Using Ig-Seq, we proteomically profiled the serological repertoire specific to the whole ectodomain of SARS-CoV-2 prefusion-stabilized spike (S) as well as to the receptor binding domain (RBD) over a 6-month period in four subjects following SARS-CoV-2 infection before SARS-CoV-2 vaccines were available. In each individual, we identified between 59 and 167 unique IgG clonotypes in serum. To our surprise, we discovered that ∼50% of serum IgG specific for RBD did not recognize prefusion-stabilized S (referred to as iso–RBD antibodies), suggesting that a significant fraction of serum IgG targets epitopes on RBD inaccessible on the prefusion-stabilized conformation of S. On the other hand, the abundance of iso–RBD antibodies in nine individuals who received mRNA-based COVID-19 vaccines encoding prefusion-stabilized S was significantly lower (∼8%). We expressed a panel of 12 monoclonal antibodies (mAbs) that were abundantly present in serum from two SARS-CoV-2 infected individuals, and their binding specificities to prefusion-stabilized S and RBD were all in agreement with the binding specificities assigned based on the proteomics data, including 1 iso–RBD mAb which bound to RBD but not to prefusion-stabilized S. 2 of 12 mAbs demonstrated neutralizing activity, while other mAbs were non-neutralizing. 11 of 12 mAbs also bound to S (B.1.351), but only 1 maintained binding to S (B.1.1.529). This particular mAb binding to S (B.1.1.529) 1) represented an antibody lineage that comprised 43% of the individual’s total S-reactive serum IgG binding titer 6 months post-infection, 2) bound to the S from a related human coronavirus, HKU1, and 3) had a high somatic hypermutation level (10.9%), suggesting that this antibody lineage likely had been elicited previously by pre-pandemic coronavirus and was re-activated following the SARS-CoV-2 infection. All 12 mAbs demonstrated their ability to engage in Fc-mediated effector function activities. Collectively, our study provides a quantitative overview of the serological repertoire following SARS-CoV-2 infection and the significant contribution of iso–RBD antibodies, demonstrating how vaccination strategies involving prefusion-stabilized S may have reduced the elicitation of iso–RBD serum antibodies which are unlikely to contribute to protection.

During a 2-year period, eight cases of a distinct illness were seen among 1,424 neonates admitted to a newly established neonatal care unit in southern Haiti. The newborns presented with a picture of sepsis with shock, vomiting, hypotonia, lethargy, and abdominal distention. Five cases proved fatal and another case left the hospital against advice in extremis with little chance of survival. In each case, the illness was associated with a history of ingestion of teas that included castor oil, known as lok in Haitian Creole. The presumptive cause of the illness was established by the presence of a dark, oily substance in drainage from the nares and nasogastric tubes and by subsequent admission on direct questioning of the caregivers, who said that the infants had been given large amounts of lok. The castor oil tea had been given to three infants in the immediate neonatal period where its use is attributed to encouraging the passage of meconium. The five remaining infants were between 15 and 30 days of life when they were given lok shortly before admission to the neonatal unit for treatment of an undefined illness. All of them were term infants with no identified risks at birth. As nasogastric tubes are not routinely placed in sick neonates, and the parents did not volunteer information about lok administration, the practice may be more widespread than that recorded here. Although our data are confined to observations in Haiti, the use of traditional medicines is a globally widespread phenomenon. Attention must be drawn to the potential toxicity of such preparations and means found to ban their use in neonates.

Background: Inactivated trivalent poliovirus vaccine (IPV) induces humoral immunity, which protects against paralytic poliomyelitis but does not induce sufficient mucosal immunity to block intestinal infection. We assessed the intestinal immunity in healthy adults in Belgium conferred by a co-formulation of IPV with the mucosal adjuvant double mutant Labile Toxin (dmLT) derived from Escherichia coli.Methods: Healthy fully IPV-vaccinated 18-45-year-olds were randomly allocated to three groups: on Day 1 two groups received one full dose of IPV (n = 30) or IPV + dmLT (n = 30) in a blinded manner, and the third received an open-label dose of bivalent live oral polio vaccine (bOPV types 1 and 3, n = 20). All groups received a challenge dose of bOPV on Day 29. Participants reported solicited and unsolicited adverse events (AE) using study diaries. Mucosal immune responses were measured by fecal neutralization and IgA on Days 29 and 43, with fecal shedding of challenge viruses measured for 28 days. Humoral responses were measured by serum neutralizing antibody (NAb).Results: Solicited and unsolicited AEs were mainly mild-to-moderate and transient in all groups, with no meaningful differences in rates between groups. Fecal shedding of challenge viruses in both IPV groups exceeded that of the bOPV group but was not different between IPV and IPV + dmLT groups. High serum NAb responses were observed in both IPV groups, alongside modest levels of fecal neutralization and IgA. Conclusions: Addition of dmLT to IPV administered intramuscularly neither affected humoral nor intestinal immunity nor decreased fecal virus shedding following bOPV challenge. The tolerability of the dose of dmLT used in this study may allow higher doses to be investigated for impact on mucosal immunity.Registered on ClinicalTrials.gov - NCT04232943.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).