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Background: Vaccine adjuvants are detected by the innate immune system and influence adaptive immune responses. The modestly efficacious RV144 Thai trial used alum to adjuvant the gp120 protein boost, whereas the non-efficacious HVTN 702 South African trial used MF59. Volunteers enrolled in HVTN 107 (NCT03284710) were administered these adjuvants with a subtype C pox-protein vaccine, affording a unique opportunity to contrast systemic innate immune responses and potentially inform the results of HVTN 702. Methods: Eighteen volunteers were enrolled per group. T1, T2 and T4 received 2 doses of ALVAC-HIV followed by 3 doses of ALVAC-HIV plus subtype C gp120 administered with MF59 (T1), alum (T2), or un-adjuvanted (T4). T3 received 4 doses of ALVAC-HIV with MF59-adjuvanted gp120. Innate immune responses were measured pre-vaccination and at days 1, 3 and 7 after the first (T3) or third (T1,T2, T4) vaccinations. Alterations in circulating leukocytes were assessed by CBC. Thirty-one serum immunomodulatory mediators were quantitated. Results: Neutrophil concentrations increased on day 1 in all groups (FDR-p's < 0.02) and monocyte concentrations increased in T2,T3 and T4 (FDR-p's < 0.12); lymphocyte concentrations significantly decreased at day 1 only in T1 (FDR-p = 0.03). Serum cytokines were also significantly altered post-vaccination in all groups (FDR-p's < 0.2). On Day 1, nine cytokines were induced in T1, including pro-inflammatory IFN-g, CXCL10, TNF-a, IL-6, as well as CCL4 and IL-2, with many factors remaining elevated at Day 3 and returning to baseline on Day 7. In contrast, only IL-2 and IL-6 were induced in T2 on Day 1 and twelve factors were repressed on Day 7 relative to pre-vaccination, including IFN-g and monocyte-chemotactic factors CCL8, CCL13, and CCL22. Responses in the MF59 groups differed when co-administered at the first vaccination (T3) relative to the third vaccination (T1) with 12 cytokines repressed on Day 1 in T3. Conclusions: Alum-adjuvanted protein administered in a prime/boost regimen including ALVAC-HIV reduced early systemic serum cytokine and chemokine responses to the vaccine, in stark contrast to MF59, where induction of a diverse immunomodulatory cytokine profile was observed in Southern African volunteers. Work on elucidating the differential effect of these two adjuvants on the types of innate immune cell responses in humans continues., OA18.03 E. Andersen-Nissen (1); V. Voillet (2); A. Naidoo (2); J. Kee (1); A. Fiore-Gartland (1); O. Dintwe (2); N. Grunenberg (1); L. Polakowski (3); L. Fleurs (4); I. Jani [...]

Background: RV144 demonstrated modest HIV preventive vaccine efficacy in Thailand. Amongst multiple identified correlates, IgG V1V2 antibodies were associated with 43% HIV risk reduction. The P5 aimed to further this by investigating subtype C vaccine regimens with different vectors (canarypox, DNA plasmid), adjuvants (alum, MF59, AS01.sub.B], or none), gp120 protein doses (40mcg, 200mcg, 600mcg), dosing strategies (prime-boost, co-administration) and administration methods (needle-syringe, Biojector). We compare IgG V1V2 responses across P5 trials with available data. Methods: In the HVTN100, HVTN107, HVTN108, and HVTN111 trials, serum specimens were obtained two weeks after the fourth vaccination. We measured the frequency and, amongst positive responders, the magnitude (MFI*: background-subtracted mean fluorescence intensity minus blank responses) of HIV-1-specific IgG (1:50 dilution) responses against V1V2 antigens for subtype C, gp70-TV1.GSKvacV1V2/293F (matched to subtype C protein vaccine), or subtype CRF01_AE, AE.A244 V1V2 Tags/293F (matched to subtype B/E protein vaccine), depending on protein administered. Responses were measured on Bio-Rad using a standardized custom Luminex HIV-1 binding antibody multiplex assay. Results: Amongst these subtype C regimens, the lowest response rate was induced by a regimen of two subtype C ALVAC primes followed by three boosts of subtype C ALVAC +200 mcg unadjuvanted gp120 (4/17 = 23.5%, CI 9.6%-47.3%); median magnitude 727.1MFI* (IQR 430.1 to 1152.1). The highest response rates were in co-administration groups of adjuvanted protein plus DNA or ALVAC at all timepoints). Rates, median magnitudes were 93.8%, 12124.8MFI* (DNA +40 mcg gp120 + [AS01.sub.B] at 3 timepoints); 91.4%, 21756.9MFI* (DNA + 200 mcg gp120 + [AS01.sub.B] at 3 timepoints); 89.1%, 7147.25MFI* (DNA + 200 mcg gp120 + MF59 by needle-syringe at 3 timepoints); 88.5%, 7745MFI* (DNA by Biojector + 200 mcg gp120 + MF59 by needle-syringe at 3 timepoints); 86.7%, 6205.1MFI* (subtype C ALVAC + 200 mcg gp120 + MF59 at 4 timepoints). For subtype C regimens, pooled response rates were higher for: (i) co-administration regimens versus regimens omitting protein in the first two doses (152/169 = 89.9% versus 233/374 = 62.3%, p < 0.00,001) and (ii) groups with DNA vaccines versus those with ALVAC (202/253 = 79.8% versus 187/299 = 62.5%, p < 0.00,001). Conclusions: Strategies which optimized IgG V1V2 responses in P5 subtype C vaccine trials included adjuvanted protein, and co-administration of adjuvanted protein + DNA or ALVAC vaccination. Responses to DNA administration by needle and syringe or Biojector were equivalent., OA18.01 F. Laher (1); C. DiazGranados (2); C. Innes (3); E. Andersen-Nissen (4); G.E. Gray (5); H. Lu (6); J. Hutter (7); K. Mngadi (3); K. Marshall (6); L. Polakowski [...]

Background: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. VRC07-523LS targets the CD4-binding site of Env and was engineered for increased breadth and half-life. In the only bnAb HIV prevention efficacy studies, the AMP studies, another CD4-binding site targeting bnAb, VRC01, was administered intravenously (IV). However, subcutaneous (SC) or intramuscular (IM) administration may be preferred. We present the first interim data comparing these routes of bnAb administration from the ongoing HVTN127/HPTN087 study. Methods: 124 healthy, HIV-uninfected participants were randomized to receive VRC07-523LS via the IV (2.5 mg/kg, 5 mg/kg, 20 mg/kg), SC (2.5 mg/kg, 5 mg/kg) or IM (2.5 mg/kg, placebo) routes. Safety data were collected for 112 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA at Day 0, 3, 6, 28, 56, 84, and 112. The log-linear portion of the time-concentration curve was used to estimate the elimination half-life. Results: Injections were well-tolerated, with mild pain or tenderness reported commonly in the SC and IM groups and mild to moderate erythema or induration reported commonly in the SC groups. Infusions were generally well-tolerated, with infusion reactions reported in 3 participants in the 20 mg/kg IV group. VRC07-523LS has an estimated median half-life of ~40 days. Median peak concentrations (with interquartile range) were 42.2 (35.1, 52.7) [mu]g/mL, 80.3 (72.3, 106.1) [mu]g/mL, and 353.6 (278.0, 461.97) [micro]g/mL for the IV groups; 11.4 (8.4, 15.2) [micro]g/mL and 24.5 (18.8, 27.0) [micro]g/mL for the SC groups; and 17.8 (15.5, 19.1) [micro]g/mL for the IM group. Geometric mean trough concentrations were 3.4 (2.5, 4.6) [micro]g/mL, 6.5 (5.6, 7.5) [micro]g/mL, and 27.2 (23.9, 31.0) [micro]g/mL for the IV groups; 0.9 (0.6, 1.4) [micro]g/mL and 3.1 (2.2, 4.3) [micro]g/mL for the SC groups; and 2.6 (2.1, 3.3) [micro]g/mL for the IM group. The peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations were highest in the IV groups and lowest in the SC groups. Conclusions: VRC07-523LS appears to be safe and well-tolerated across a range of doses and routes and is a promising bnAb for inclusion in HIV-1 prevention regimens., OA03.01 S. Walsh (1); C. Gay (2); S. Karuna (3); O. Hyrien (3); T. Skalland (3); K.H. Mayer (4); M. Sobieszczyk (5); P. Andrew (6); C. Karg (3); J. Baumblatt [...]

Background: The partially efficacious RV144 HIV-1 vaccine trial utilized a gp120 protein boost adjuvanted with alum, whereas the non-efficacious HVTN 702 preventive HIV vaccine utilized a gp120 protein boost adjuvanted with MF59. We compared Env-specific IgG and IgA responses in HVTN 107, a phase 1/2a partially double-blinded clinica trial, utilizing a Clade C ALVAC-HIV prime and 100 mcg gp120 protein boost adjuvanted with alum or MF59 vs. a protein-only boost. Methods: We randomized 132 participants into 4 groups and analyzed Env-specific IgG and IgA binding antibodies at Months 6.5 and 12 (NCT03284710). Results: Robust IgG (96.3% to 100%) and IgA (92% to 93%) responses were seen for all trial arms at the month 6.5 timepoint to gp120 Env proteins contained in the vaccine regimen (ZM96, TV1.C and 1086.C). Compared to all other trial arms, T3 (MF59-adjuvanted co-administration) exhibited significantly greater response rates and magnitudes to vaccine-matched Env proteins at the month 12 time-point. Comparable IgG response rates and magnitudes to vaccine-matched Env proteins were observed between the alum and MF59 prime-boost trial arms. Compared to other groups, T3 exhibited significantly higher IgG response rates to V1V2 panel antigens gp70_B.CaseA_V1V2 (83% vs. 18%-48%, p Conclusions: Env-specific antibody response rates between Alum and MF59-adjuvanted vaccine regimens were similar, including V1V2 IgG response rates that correlated with decreased HIV risk in RV144. On the other hand, co-administration of ALVAC-HIV with gp120 in MF59 induced the highest antibody response rates and magnitudes. Additional studies of vaccine-elicited antibody specificity and function will inform adjuvant-specific induction of potentially protective humoral immune responses., OA18.02 P. Goepfert (1); K. Mngadi (2); Z. Moodie (3); N. Grunenberg (3); J.J. Kee (3); K. Seaton (4); G. Tomaras (4); E. Andersen-Nissen (5); O. Dintwe (5); F. Laher [...]

Background: The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a novel glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV., Methods: HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants in South Africa aged ≤5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks., Results: 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, p = 0.25; 4, 40.0% systemic, p = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded., Conclusions: This study illustrates the feasibility of conducting trials of novel adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring., Trial Registration: ClinicalTrials.gov NCT04607408., Funding: National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH)., Competing Interests: Declaration of interests OL is a named inventor on patents relating to vaccine adjuvants and to human in vitro systems that model the safety and immunogenicity of adjuvants, vaccines and immunomodulators. He serves as a consultant to GSK and Hillevax and is a co-founder of Ovax, Inc. All other authors declare no conflict of interest.

Elucidating optimal vaccine adjuvants for harnessing age-specific immune pathways to enhance magnitude, breadth, and durability of immunogenicity remains a key gap area in pediatric vaccine design. A better understanding of age-specific adjuvants will inform precision discovery and development of safe and effective vaccines for protecting children from preventable infectious diseases.

Background: Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes., Methods: This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA. Participants were randomly assigned (per prespecified randomisation ratios within enrolment waves) according to a computer-generated randomisation scheme, stratified by age (<65 years and ≥65 years), to various intravenous or subcutaneous doses of casirivimab and imdevimab before, after, or at the same time as mRNA-1273 or to mRNA-1273 only. The doses of casirivimab and imdevimab were chosen to mimic various time intervals between receipt of 1200 mg of the mAb and the first dose of a primary series with mRNA-1273. The primary endpoint was vaccine-induced 50% inhibitory dilution neutralising antibody titres to SARS-CoV-2 spike protein, 56 days after the first vaccination. Secondary endpoints included vaccine-induced total antibodies to SARS-CoV-2 antigens and incidence of treatment-emergent adverse events. Exploratory endpoints included blood-derived T-cell and B-cell responses. The per-protocol set was used for the analysis of the primary endpoint and included all randomly assigned participants who received both doses of the vaccine and completed the injection or infusion of casirivimab and imdevimab per protocol, had no evidence of SARS-CoV-2 infection in the past or in the 56 days after the first dose of vaccine, and did not receive any intervention outside of the study that could alter the immune response. Safety was assessed in the safety analysis set, which included all randomly assigned participants who had received one or more doses of mRNA-1273 or any study drug, and analysed based on treatment received. The study is registered with ClinicalTrials.gov, NCT04852978, and is complete., Findings: Between April 29, 2021, and Nov 21, 2022, 807 participants were assessed for eligibility and 295 were randomly assigned. 293 participants were included in the safety analysis set and 260 were included in the per-protocol set. All vaccinated participants developed neutralising antibodies to SARS-CoV-2, with median titres above the published protective threshold (100 IU/mL) against the SARS-CoV-2 D614G variant (considered a reference strain at the time the initial COVID-19 vaccines were developed). Titres were decreased up to 4-fold (median titres 280-450 IU/mL for casirivimab and imdevimab vs 1160 IU/mL for vaccine only on day 56) when casirivimab and imdevimab was given 85 days or less before vaccination (150-1200 mg intravenously) or co-administered subcutaneously (600 mg or 1200 mg) with vaccination. Minimal reduction in neutralisation titres was observed in the 48 mg and 12 mg intravenous groups, corresponding to receipt of casirivimab and imdevimab 113 days and 169 days, respectively, before vaccination, and when administering the vaccine 6 days before the mAb. Across all groups, mAbs had a minimal effect on vaccine-induced total antibodies and T-cell responses to the spike protein. Casirivimab and imdevimab plus mRNA-1273 was generally well tolerated; a slight increase in treatment-emergent adverse events was observed in the casirivimab and imdevimab plus vaccine groups versus the vaccine-only group., Interpretation: Casirivimab and imdevimab administration before or at the time of COVID-19 vaccination reduced the elicitation of SARS-CoV-2 neutralising antibodies, but minimal effect was observed when vaccination occurred before mAb administration. Although the clinical significance of this decrease in neutralisation is unclear, this evidence suggests that further investigation of potential interactions could be warranted before concurrent clinical use of mAbs and vaccines targeting the same viral proteins as their main modes of action for the prevention or treatment of infectious diseases., Funding: Regeneron Pharmaceuticals and F Hoffmann-La Roche., Competing Interests: Declaration of interests FI and JDH are employees and stockholders of Regeneron Pharmaceuticals, and report having patents pending, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. AMGO, BAO, TB, SG, LF, SCI, MT, GPG, and BM are employees and stockholders of Regeneron Pharmaceuticals. JM is an employee of Regeneron Pharmaceuticals. EF-N is a former employee and current stockholder of Regeneron Pharmaceuticals, and reports patents pending, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. IH is an employee and stockholder of Regeneron Pharmaceuticals, and a stockholder of Merck & Co. ATH is an employee and stockholder of Regeneron Pharmaceuticals, is a stockholder of Pfizer, and reports a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals. AB, CAK, and GDY are employees and stockholders of Regeneron Pharmaceuticals and report having issued patents (US patent numbers 10 787 501, 10 954 289, and 10 975 139) and pending patents, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. CDP is an employee and stockholder of Regeneron Pharmaceuticals and reports a patent pending with Regeneron Pharmaceuticals. MJM reports funding from Regeneron Pharmaceuticals, paid to her institution, and grants from the US National Institute of Allergy and Infectious Diseases, the Biomedical Advanced Research and Development Authority, Moderna, Sanofi Pasteur, and Janssen, paid to her institution. SCDR reports grants from the National Institutes of Health and the Bill & Melinda Gates Foundation awarded to his institution, and contracts from Regeneron Pharmaceuticals, The Henry M Jackson Foundation, Johnson & Johnson Innovative Medicine (formerly Janssen Pharmaceuticals), Gates Medical Research Institute, Paul G Allen Family Foundation, and Battelle, awarded to his institution. KWC reports funding from Regeneron Pharmaceuticals, paid to her institution, and is an employee and stockholder of Moderna. LDW CAH, AJO, AHP, and GDT report funding and provision of study materials from Regeneron Pharmaceuticals, paid to their institution. GAH is an employee and stockholder of Regeneron Pharmaceuticals and reports having a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, as well as a pending patent application. MM, JH, LP, and FAF declare no competing interests., (Copyright © 2024. Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: HVTN 120 is a phase 1/2a randomized double-blind placebo-controlled human immunodeficiency virus (HIV) vaccine trial that evaluated the safety and immunogenicity of ALVAC-HIV (vCP2438) and MF59- or AS01B-adjuvanted bivalent subtype C gp120 Env protein at 2 dose levels in healthy HIV-uninfected adults., Methods: Participants received ALVAC-HIV (vCP2438) alone or placebo at months 0 and 1. At months 3 and 6, participants received either placebo, ALVAC-HIV (vCP2438) with 200 μg of bivalent subtype C gp120 adjuvanted with MF59 or AS01B, or ALVAC-HIV (vCP2438) with 40 μg of bivalent subtype C gp120 adjuvanted with AS01B. Primary outcomes were safety and immune responses., Results: We enrolled 160 participants, 55% women, 18-40 years old (median age 24 years) of whom 150 received vaccine and 10 placebo. Vaccines were generally safe and well tolerated. At months 6.5 and 12, CD4+ T-cell response rates and magnitudes were higher in the AS01B-adjuvanted groups than in the MF59-adjuvanted group. At month 12, HIV-specific Env-gp120 binding antibody response magnitudes in the 40 μg gp120/AS01B group were higher than in either of the 200 μg gp120 groups., Conclusions: The 40 μg dose gp120/AS01B regimen elicited the highest CD4+ T-cell and binding antibody responses. Clinical Trials Registration . NCT03122223., Competing Interests: Potential conflicts of interest. S. G. is an employee of Sanofi Pasteur and C. A. D. G. was employed by Sanofi Pasteur at the time of the study. M. Ko. and O. V. D. M. are employees of GSK and hold shares in GSK. All other authors report no potential conflicts. Funding to pay the Open Access publication charges for this article was provided by the NIH. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Adjuvants are widely used to enhance and/or direct vaccine-induced immune responses yet rarely evaluated head-to-head. Our trial directly compared immune responses elicited by MF59 versus alum adjuvants in the RV144-like HIV vaccine regimen modified for the Southern African region. The RV144 trial of a recombinant canarypox vaccine vector expressing HIV env subtype B (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost adjuvanted with alum is the only trial to have shown modest HIV vaccine efficacy. Data generated after RV144 suggested that use of MF59 adjuvant might allow lower protein doses to be used while maintaining robust immune responses. We evaluated safety and immunogenicity of an HIV recombinant canarypox vaccine vector expressing HIV env subtype C (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost (gp120) adjuvanted with alum (ALVAC-HIV+gp120/alum) or MF59 (ALVAC-HIV+gp120/MF59) or unadjuvanted (ALVAC-HIV+gp120/no-adjuvant) and a regimen where ALVAC-HIV+gp120 adjuvanted with MF59 was used for the prime and boost (ALVAC-HIV+gp120/MF59 coadministration)., Methods and Findings: Between June 19, 2017 and June 14, 2018, 132 healthy adults without HIV in South Africa, Zimbabwe, and Mozambique were randomized to receive intramuscularly: (1) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/MF59 (months 3, 6, and 12), n = 36; (2) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/alum (months 3, 6, and 12), n = 36; (3) 4 doses of ALVAC-HIV+gp120/MF59 coadministered (months 0, 1, 6, and 12), n = 36; or (4) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/no adjuvant (months 3, 6, and 12), n = 24. Primary outcomes were safety and occurrence and mean fluorescence intensity (MFI) of vaccine-induced gp120-specific IgG and IgA binding antibodies at month 6.5. All vaccinations were safe and well-tolerated; increased alanine aminotransferase was the most frequent related adverse event, occurring in 2 (1.5%) participants (1 severe, 1 mild). At month 6.5, vaccine-specific gp120 IgG binding antibodies were detected in 100% of vaccinees for all 4 vaccine groups. No significant differences were seen in the occurrence and net MFI of vaccine-specific IgA responses between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/alum-prime-boost groups or between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/MF59 coadministration groups. Limitations were the relatively small sample size per group and lack of evaluation of higher gp120 doses., Conclusions: Although MF59 was expected to enhance immune responses, alum induced similar responses to MF59, suggesting that the choice between these adjuvants may not be critical for the ALVAC+gp120 regimen., Trial Registration: HVTN 107 was registered with the South African National Clinical Trials Registry (DOH-27-0715-4894) and ClinicalTrials.gov (NCT03284710)., Competing Interests: MK and OVDM are employed by GSK and hold shares in the company. MK reports grants from Bill & Melinda Gates Foundation and grants from NIH during the conduct of the study. NKT was an employee of GSK Biologicals and Novartis Vaccines & Diagnostics during the time of the trial. All other authors have nothing to declare., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Post-COVID conditions are characterised by persistent symptoms that negatively impact quality of life after SARS-CoV-2 diagnosis. While post-COVID risk factors and symptoms have been extensively described in localised regions, especially in the global north, post-COVID conditions remain poorly understood globally. The global, observational cohort study HVTN 405/HPTN 1901 characterises the convalescent course of SARS-CoV-2 infection among adults in North and South America and Africa., Methods: We categorised the cohort by infection severity (asymptomatic, symptomatic, no oxygen requirement (NOR), non-invasive oxygen requirement (NIOR), invasive oxygen requirement (IOR)). We applied a regression model to assess correlations of demographics, co-morbidities, disease severity, and concomitant medications with COVID-19 symptom persistence and duration across global regions., Results: We enrolled 759 participants from Botswana, Malawi, South Africa, Zambia, Zimbabwe, Peru, and the USA a median of 51 (interquartile range (IQR) = 35-66) days post-diagnosis, from May 2020 to March 2021. 53.8% were female, 69.8% were 18-55 years old (median (md) = 44 years old, IQR = 33-58). Comorbidities included obesity (42.8%), hypertension (24%), diabetes (14%), human immunodeficiency virus (HIV) infection (11.6%) and lung disease (7.5%). 76.2% were symptomatic (NOR = 47.4%; NIOR = 22.9%; IOR = 5.8%). Median COVID-19 duration among symptomatic participants was 20 days (IQR = 11-35); 43.4% reported symptoms after COVID-19 resolution, 33.6% reported symptoms ≥30 days, 9.9% reported symptoms ≥60 days. Symptom duration correlated with disease severity (P < 0.001, NIOR vs NOR; P = 0.003, IOR vs NOR), lung disease (P = 0.001), race (P < 0.05, non-Hispanic Black vs White), and global region (P < 0.001). Prolonged viral shedding correlated with persistent abdominal pain (odds ratio (OR) = 5.51, P < 0.05) and persistent diarrhoea (OR = 6.64, P < 0.01)., Conclusions: Post-COVID duration varied with infection severity, race, lung disease, and region. Better understanding post-COVID conditions, including regionally-diverse symptom profiles, may improve clinical assessment and management globally., Registration: Clinicaltrials.gov (#NCT04403880)., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and declare the following activities and relationships: PG reports funding from HVTN, consulting fees from Johnson & Johnson and DSMB activities. The other authors declare no conflicts of interest: KG, CK, JH, LP, MT, PH, RD, JGC, JM, LC, MJ, SL, VK, JH, MDM, SK, DT, NE, AT, RM., (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

Background: People infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) experience a wide range of clinical manifestations, from asymptomatic and mild illness to severe illness and death, influenced by age and a variety of comorbidities. Neutralizing antibodies (nAbs) are thought to be a primary immune defense against the virus. Large, diverse, well-characterized cohorts of convalescent individuals provide standardized values to benchmark nAb responses to past SARS-CoV-2 infection and define potentially protective levels of immunity., Methods and Findings: This analysis comprises an observational cohort of 329 HIV-seronegative adults in the United States (n = 167) and Peru (n = 162) convalescing from SARS-CoV-2 infection from May through October 2020. The mean age was 48 years (range 18 to 86), 54% of the cohort overall was Hispanic, and 34% identified as White. nAb titers were measured in serum by SARS-CoV-2.D614G Spike-pseudotyped virus infection of 293T/ACE2 cells. Multiple linear regression was applied to define associations between nAb titers and demographic variables, disease severity and time from infection or disease onset, and comorbidities within and across US and Peruvian cohorts over time. nAb titers peaked 28 to 42 days post-diagnosis and were higher in participants with a history of severe Coronavirus Disease 2019 (COVID-19) (p < 0.001). Diabetes, age >55 years, male sex assigned at birth, and, in some cases, body mass index were also independently associated with higher nAb titers, whereas hypertension was independently associated with lower nAb titers. nAb titers did not differ by race, underlying pulmonary disease or smoking. Two months post-enrollment, nAb ID50 (ID80) titers declined 3.5 (2.8)-fold overall. Study limitations in this observational, convalescent cohort include survivorship bias and missing early viral loads and acute immune responses to correlate with the convalescent responses we observed., Conclusions: In summary, in our cohort, nAb titers after SARS-CoV-2 infection peaked approximately 1 month post-diagnosis and varied by age, sex assigned at birth, disease severity, and underlying comorbidities. Our data show great heterogeneity in nAb responses among people with recent COVID-19, highlighting the challenges of interpreting natural history studies and gauging responses to vaccines and therapeutics among people with recent infection. Our observations illuminate potential correlations of demographic and clinical characteristics with nAb responses, a key element for protection from COVID-19, thus informing development and implementation of preventative and therapeutic strategies globally., Trial Registration: ClinicalTrials.gov NCT04403880., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: IF serves on advisory boards for Gilead and ViiV and receives grant money from Sanofi, Janssen and Moderna. SRW has received funding from NIH/NIAID as well as the Bill and Melinda Gates Foundation unrelated to this work; he has also conducted clinical trials funded by Janssen, Sanofi Pasteur, and Regeneron, also unrelated to this work. SK, LF, AKR, SG, LC, JGK, LP, MC, DM, OH, SSL, MT, MDM declare no conflicts of interest.

Background: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported., Methods: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021., Results: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified., Conclusions: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Eliciting durable humoral immunity with sufficient breadth and magnitude is important for HIV-1 vaccine design. The HVTN 114 vaccine trial evaluated different boost regimens administered after a 7-year rest period in participants previously enrolled in HVTN 205, who received either three MVA/HIV62B (MMM) or two DNA and two MVA/HIV62B (DDMM) injections; both vaccines expressed multiple HIV-1 antigens in non-infectious virus-like-particles. The primary objective of HVTN 114 was to assess the impact of a heterologous gp120 protein AIDSVAX B/E boost on the magnitude, breadth and durability of vaccine-induced immune responses., Methods: We enrolled 27 participants from HVTN 205 into five groups. Eight participants who previously received MMM were randomized and boosted with either MVA/HIV62B alone (T1; n = 4) or MVA/HIV62B and AIDSVAX B/E (T2; n = 4). Nineteen participants who received DDMM were randomized and boosted with MVA/HIV62B alone (T3; n = 6), MVA/HIV62B and AIDSVAX B/E (T4; n = 6), or AIDSVAX B/E alone (T5; n = 7). Boosts were at months 0 and 4. Participants were followed for safety and immunogenicity for 10 months and were pooled for analysis based on the regimen: MVA-only (T1 + T3), MVA + AIDSVAX (T2 + T4), and AIDSVAX-only (T5)., Results: All regimens were safe and well-tolerated. Prior to the boost vaccination, binding antibody and CD4+T-cell responses were observed 7 years after HVTN 205 vaccinations. Late boosting with AIDSVAX, with or without MVA, resulted in high binding antibody responses to gp120 and V1V2 epitopes, with increased magnitude and breadth compared to those observed in HVTN 205. Late boosting with MVA, with or without AIDSVAX, resulted in increased gp140 and gp41 antibody responses and higher CD4+T-cell responses to Env and Gag., Conclusions: Late boosting with AIDSVAX, alone or in combination with MVA, can broaden binding antibody responses and increase T-cell responses even years following the original MVA/HIV62B with or without DNA-priming vaccine., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [The authors of this manuscript have read the journal's policy and have the following competing interests: YH, CY, MDM, CP, SCD, KC, MJM, PG, JM, MK, MS, LRB, DM are recipients of funding from The National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, and this publication is a result of activities funded by the NIAID. HLR was a co-founder of GeoVax, Inc. and is an inventor on patents that GeoVax licensed from Emory University and the NIAID for commercial development of the MVA/HIV62B and JS7 DNA vaccines. CFK receives research grants to her institution from NIH, CDC, Gilead Sciences, ViiV, Moderna, and Novavax. GDT received research grants to her institution from NIAID, BMGF, GSK and Macrogenics, has patent applications for HIV vaccine design and incidence testing, and has consulted for Axon Advisors. KES has a patent application for HIV incidence testing. SB receives research grants to her institution from NIH, Gilead Sciences, Merck, and Viiv. The rest of the authors have no conflicts., (Published by Elsevier Ltd.)

We studied mucosal immune responses in six HIV-1 vaccine trials investigating different envelope (Env)-containing immunogens. Regimens were classified into four categories: DNA/vector, DNA/vector plus protein, protein alone, and vector alone. We measured HIV-1-specific IgG and IgA in secretions from cervical (n = 111) and rectal swabs (n = 154), saliva (n = 141), and seminal plasma (n = 124) and compared to corresponding blood levels. Protein-containing regimens had up to 100% response rates and the highest Env-specific IgG response rates. DNA/vector groups elicited mucosal Env-specific IgG response rates of up to 67% that varied across specimen types. Little to no mucosal IgA responses were observed. Overall, gp41- and gp140-specific antibodies dominated gp120 mucosal responses. In one trial, prior vaccination with a protein-containing immunogen maintained durability of cervical and rectal IgG for up to 17 years. Mucosal IgG responses were boosted after revaccination. These findings highlight a role for protein immunization in eliciting HIV-1-specific mucosal antibodies and the ability of HIV-1 vaccines to elicit durable HIV-1-specific mucosal IgG.

Background: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19., Methods: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2., Results: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups., Conclusions: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Several techniques are under investigation to improve the immunogenicity of HIV-1 DNA vaccine candidates. DNA vaccines are advantageous due to their ease of design, expression of multiple antigens, and safety., Methods: The HVTN 098 trial assessed the PENNVAX ® -GP DNA vaccine (encoding HIV env , gag , pol ) administered with or without plasmid IL-12 at 0-, 1-, 3-, and 6-month timepoints via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, adult participants. We report on safety, tolerability, and acceptability., Results: HVTN 098 enrolled 94 participants: 85 received PENNVAX ® -GP and nine received placebo. Visual analog scale (VAS) pain scores immediately after each vaccination were lower in the ID/EP than in the IM/EP group (medians 4.1-4.6 vs. 6-6.5, p < 0.01). IM/EP participants reported greater pain and/or tenderness at the injection site. Most ID/EP participants had skin lesions such as scabs/eschars, scars, and pigmentation changes, which resolved within 6 months in 51% of participants (24/55). Eighty-two percent of IM/EP and 92% of ID/EP participant survey responses showed acceptable levels of discomfort., Conclusions: ID/EP and IM/EP are distinct experiences; however, HIV-1 DNA vaccination by either route was safe, tolerable and acceptable by most study participants.

BACKGROUNDHVTN 098, a randomized, double-blind, placebo-controlled trial, evaluated the safety, tolerability, and immunogenicity of PENNVAX-GP HIV DNA vaccine, administered with or without plasmid IL-12 (pIL-12), via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, HIV-uninfected adults. The study tested whether PENNVAX-GP delivered via ID/EP at one-fifth the dose could elicit equivalent immune responses to delivery via IM/EP and whether inclusion of pIL-12 provided additional benefit.METHODSParticipants received DNA encoding HIV-1 env/gag/pol in 3 groups: 1.6 mg ID (ID no IL-12 group, n = 20), 1.6 mg ID + 0.4 mg pIL-12 (ID + IL-12 group, n = 30), 8 mg IM + 1 mg pIL-12 (IM + IL-12 group, n = 30), or placebo (n = 9) via EP at 0, 1, 3, and 6 months. Results of cellular and humoral immunogenicity assessments are reported.RESULTSFollowing vaccination, the frequency of responders (response rate) to any HIV protein based on CD4+ T cells expressing IFN-γ or IL-2 was 96% for both the ID + IL-12 and IM + IL-12 groups; CD8+ T cell response rates were 64% and 44%, respectively. For ID delivery, the inclusion of pIL-12 increased CD4+ T cell response rate from 56% to 96%. The frequency of responders was similar (≥90%) for IgG binding antibody to gp140 consensus Env across all groups, but the magnitude was higher in the ID + IL-12 group compared with the IM + IL-12 group.CONCLUSIONPENNVAX-GP DNA induced robust cellular and humoral immune responses, demonstrating that immunogenicity of DNA vaccines can be enhanced by EP route and inclusion of pIL-12. ID/EP was dose sparing, inducing equivalent, or in some aspects superior, immune responses compared with IM/EP.TRIAL REGISTRATIONClinicalTrials.gov NCT02431767.FUNDINGThis work was supported by National Institute of Allergy and Infectious Diseases (NIAID), U.S. Public Health Service grants, an HIV Vaccine Design and Development Team contract, Integrated Preclinical/Clinical AIDS Vaccine Development Program, and an NIH award.