Heterologous Ad26.COV2.S booster after primary BBIBP-CorV vaccination against SARS-CoV-2 infection: 1-year follow-up of a phase 1/2 open-label trial.

BACKGROUND: Inactivated whole-virus vaccination elicits immune responses to both SARS-CoV-2 nucleocapsid (N) and spike (S) proteins, like natural infections. A heterologous Ad26.COV2.S booster given at two different intervals after primary BBIBP-CorV vaccination was safe and immunogenic at days 28 and 84, with higher immune responses observed after the longer pre-boost interval. We describe booster-specific and hybrid immune responses over 1 year. METHODS: This open-label phase 1/2 study was conducted in healthy Thai adults aged ≥ 18 years who had completed primary BBIBP-CorV primary vaccination between 90-240 (Arm A1; n = 361) or 45-75 days (Arm A2; n = 104) before enrolment. All received an Ad26.COV2.S booster. We measured anti-S and anti-N IgG antibodies by Elecsys®, neutralizing antibodies by SARS-CoV-2 pseudovirus neutralization assay, and T-cell responses by quantitative interferon (IFN)-γ release assay. Immune responses were evaluated in the baseline-seronegative population (pre-booster anti-N < 1.4 U/mL; n = 241) that included the booster-effect subgroup (anti-N < 1.4 U/mL at each visit) and the hybrid-immunity subgroup (anti-N ≥ 1.4 U/mL and/or SARS-CoV-2 infection, irrespective of receiving non-study COVID-19 boosters). RESULTS: In Arm A1 of the booster-effect subgroup, anti-S GMCs were 131-fold higher than baseline at day 336; neutralizing responses against ancestral SARS-CoV-2 were 5-fold higher than baseline at day 168; 4-fold against Omicron BA.2 at day 84. IFN-γ remained approximately 4-fold higher than baseline at days 168 and 336 in 18-59-year-olds. Booster-specific responses trended lower in Arm A2. In the hybrid-immunity subgroup at day 336, anti-S GMCs in A1 were 517-fold higher than baseline; neutralizing responses against ancestral SARS-CoV-2 and Omicron BA.2 were 28- and 31-fold higher, respectively, and IFN-γ was approximately 14-fold higher in 18-59-year-olds at day 336. Durable immune responses trended lower in ≥ 60-year-olds. CONCLUSION: A heterologous Ad26.COV2.S booster after primary BBIBP-CorV vaccination induced booster-specific immune responses detectable up to 1 year that were higher in participants with hybrid immunity. CLINICAL TRIALS REGISTRATION: NCT05109559.

Effect of homologous or heterologous vaccine booster over two initial doses of inactivated COVID-19 vaccine.

INTRODUCTION: Inactivated vaccines were delivered to low- and middle-income countries during the early pandemics of COVID-19. Currently, more than 10 inactivated COVID-19 vaccines have been developed. Most inactivated vaccines contain an inactivated whole-cell index SARS-CoV-2 strain that is adjuvant. Whole virions inactivated with aluminum hydroxide vaccines were among the most commonly used. However, with the emerging of COVID-19 variants and waning of the immunity of two doses of after 3 months, WHO and many local governments have recommended the booster-dose program especially with heterologous platform vaccine. AREA COVERED: This review was conducted through a literature search of the MEDLINE database to identify articles published from 2020 to 2023 covered the inactivated COVID-19 vaccines primary series with homologous and heterologous booster focusing on safety, immunogenicity, efficacy, and effectiveness. EXPERT OPINION: The inactivated vaccines, especially whole virion inactivated in aluminum hydroxide appeared to be safe and had good priming effects. Immune responses generated after one dose of heterologous boost were high and able to preventing severity of disease and symptomatic infection. A new approach to inactivated vaccine has been developed using inactivating recombinant vector virus-NDV-HXP-S vaccine.

Innate immune cell activation after HIV-1 vaccine administration is associated with increased antibody production.

The RV144 Thai phase III clinical trial's canarypox-protein HIV vaccine regimen showed modest efficacy in reducing infection. We therefore sought to determine the effects of vaccine administration on innate cell activation and subsequent associations with vaccine-induced immune responses. RV306 was a randomized, double-blind clinical trial in HIV-uninfected Thai adults that tested delayed boosting following the RV144 regimen. PBMC collected from RV306 participants prior to and 3 days after the last boost were used to investigate innate immune cell activation. Our analysis showed an increase in CD38+ mucosal associated invariant T (MAIT) cells, CD38+ invariant natural killer T (iNKT) cells, CD38+ γδ T cells, CD38+, CD69+ and HLA-DR+ NK cells 3 days after vaccine administration. An increase in CD14-CD16+ non-classical monocytes and CD14+CD16+ intermediate monocytes accompanied by a decrease in CD14+CD16- classical monocytes was also associated with vaccine administration. Inclusion of ALVAC-HIV in the boost did not further increase MAIT, iNKT, γδ T, and NK cell activation or increase the proportion of non-classical monocytes. Additionally, NK cell activation 3 days after vaccination was positively associated with antibody titers of HIV Env-specific total IgG and IgG1. Vδ1 T cell activation 3 days after vaccine administration was associated with HIV Env-specific IgG3 titers. Finally, we observed trending associations between MAIT cell activation and Env-specific IgG3 titers and between NK cell activation and TH023 pseudovirus neutralization titers. Our study identifies a potential role for innate cells, specifically NK, MAIT, and γδ T cells, in promoting antibody responses following HIV-1 vaccine administration.

The Brighton collaboration standardized module for vaccine benefit-risk assessment.

Vaccine Benefit-Risk (B-R) assessment consists of evaluating the benefits and risks of a vaccine and making a judgment whether the expected key benefits outweigh the potential key risks associated with its expected use. B-R supports regulatory and public health decision-making throughout the vaccine's lifecycle. In August 2021, the Brighton Collaboration's Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Benefit-Risk Assessment Module working group was established to develop a standard module to support the planning, conduct and evaluation of structured B-R assessments for vaccines from different platforms, based on data from clinical trials, post-marketing studies and real-world evidence. It enables sharing of relevant information via value trees, effects tables and graphical depictions of B-R trade-offs. It is intended to support vaccine developers, funders, regulators and policy makers in high-, middle- or low-income countries to help inform decision-making and facilitate transparent communication concerning development, licensure, deployment and other lifecycle decisions.

Ten-Year Follow-up of 9-Valent Human Papillomavirus Vaccine: Immunogenicity, Effectiveness, and Safety.

BACKGROUND AND OBJECTIVES: The 9-valent human papillomavirus (9vHPV) vaccine Phase III immunogenicity study in 9- to 15-year-old boys and girls was extended to assess immunogenicity and effectiveness through 10 years after the last vaccine dose (NCT00943722). METHODS: Boys (n = 301) and girls (n = 971) who received three 9vHPV vaccine doses in the base study (day 1, months 2 and 6) enrolled in the extension. Serum was collected through month 126 for antibody assessments by competitive Luminex immunoassay and immunoglobulin G-Luminex immunoassay. For effectiveness analysis starting at age 16 years, genital swabs were collected (to assess HPV DNA by polymerase chain reaction) and external genital examinations conducted every 6 months. Primary analyses were conducted in per-protocol populations. RESULTS: Geometric mean antibody titers peaked around month 7, decreased sharply between months 7 and 12, then gradually through month 126. Seropositivity rates remained ≥81% by competitive Luminex immunoassay and ≥95% by immunoglobin G-Luminex immunoassay at month 126 for each 9vHPV vaccine type. After up to 11.0 (median 10.0) years of follow-up postdose 3, there were no cases of HPV6/11/16/18/31/33/45/52/58-related high-grade intraepithelial neoplasia or condyloma in males or females. Incidence rates of HPV6/11/16/18/31/33/45/52/58-related 6-month persistent infection in males and females were low (54.6 and 52.4 per 10000 person-years, respectively) and within ranges expected in vaccinated cohorts, based on previous human papillomavirus vaccine efficacy trials. CONCLUSIONS: The 9vHPV vaccine demonstrated sustained immunogenicity and effectiveness through ∼10 years post 3 doses of 9vHPV vaccination of boys and girls aged 9 to 15 years.

Single Ad26.COV2.S booster dose following two doses of BBIBP-CorV vaccine against SARS-CoV-2 infection in adults: Day 28 results of a phase 1/2 open-label trial.

BACKGROUND: The inactivated COVID-19 whole-virus vaccine BBIBP-CorV has been extensively used worldwide. Heterologous boosting after primary vaccination can induce higher immune responses against SARS-CoV-2 than homologous boosting. The safety and immunogenicity after 28 days of a single Ad26.COV2.S booster dose given at different intervals after 2 doses of BBIBP-CorV are presented. METHODS: This open-label phase 1/2 trial was conducted in healthy adults in Thailand who had completed 2-dose primary vaccination with BBIBP-CorV. Participants received a single booster dose of Ad26.COV2.S (5 × 1010 virus particles) 90-240 days (Group A1; n = 360) or 45-75 days (Group A2; n = 66) after the second BBIBP-CorV dose. Safety and immunogenicity were assessed over 28 days. Binding IgG antibodies to the full-length pre-fusion Spike and anti-nucleocapsid proteins of SARS-CoV-2 were measured by enzyme-linked immunosorbent assay. The SARS-CoV-2 pseudovirus neutralization assay and live virus microneutralization assay were used to quantify the neutralizing activity of antibodies against ancestral SARS-CoV-2 (Wuhan-Hu-1) and the delta (B.1.617.2) and omicron (B.1.1.529/BA.1 and BA.2) variants. The cell-mediated immune response was measured using a quantitative interferon (IFN)-γ release assay in whole blood. RESULTS: Solicited local and systemic adverse events (AEs) on days 0-7 were mostly mild, as were unsolicited vaccine-related AEs during days 0-28, with no serious AEs. On day 28, anti-Spike binding antibodies increased from baseline by 487- and 146-fold in Groups A1 and A2, and neutralizing antibodies against ancestral SARS-CoV-2 by 55- and 37-fold, respectively. Humoral responses were strongest against ancestral SARS-CoV-2, followed by the delta, then the omicron BA.2 and BA.1 variants. T-cell-produced interferon-γ increased approximately 10-fold in both groups. CONCLUSIONS: A single heterologous Ad26.COV2.S booster dose after two BBIBP-CorV doses was well tolerated and induced robust humoral and cell-mediated immune responses measured at day 28 in both interval groups. CLINICAL TRIALS REGISTRATION: NCT05109559.

Considerations for unblinding individual study participants during vaccine trials.

Premature unblinding of individual participants is rarely reported in publications, but such unblinding can disrupt vaccine trials by causing worry and drop-out of other participants or "pseudo unblinding," in which participants or investigators over-interpret certain symptoms as being related to receiving an investigational product. This review summarizes appropriate reasons for unblinding in vaccine trials. Regulatory guidance could be improved by distinguishing guidance for vaccine trials from drug trials, with the recognition that unblinding individual participants in vaccine studies is rarely needed for management of adverse events following immunization.

An inactivated NDV-HXP-S COVID-19 vaccine elicits a higher proportion of neutralizing antibodies in humans than mRNA vaccination.

NDV-HXP-S is a recombinant Newcastle disease virus-based vaccine against SARS-CoV-2, which expresses an optimized (HexaPro) spike protein on its surface. The vaccine can be produced in embryonated chicken eggs using the same process as that used for the production of the vast majority of influenza virus vaccines. Here, we performed a secondary analysis of the antibody responses after vaccination with inactivated NDV-HXP-S in a phase 1 clinical study in Thailand. The SARS-CoV-2 neutralizing and spike protein binding activity of NDV-HXP-S postvaccination serum samples was compared to that of samples from mRNA BNT162b2 (Pfizer) vaccinees. Neutralizing activity of sera from NDV-HXP-S vaccinees was comparable to that of BNT162b2 vaccinees, whereas spike protein binding activity of the NDV-HXP-S vaccinee samples was lower than that of sera obtained from mRNA vaccinees. This led us to calculate ratios between binding and neutralizing antibody titers. Samples from NDV-HXP-S vaccinees had binding to neutralizing activity ratios that were lower than those of BNT162b2 sera, suggesting that NDV-HXP-S vaccination elicits a high proportion of neutralizing antibodies and low non-neutralizing antibody titers. Further analysis showed that, in contrast to mRNA vaccination, which induces strong antibody titers to the receptor binding domain (RBD), the N-terminal domain, and the S2 domain, NDV-HXP-S vaccination induced an RBD-focused antibody response with little reactivity to S2. This finding may explain the high proportion of neutralizing antibodies. In conclusion, vaccination with inactivated NDV-HXP-S induces a high proportion of neutralizing antibodies and absolute neutralizing antibody titers that are comparable to those elicited by mRNA vaccination.

Immunogenicity of a fractional or full third dose of AZD1222 vaccine or BNT162b2 messenger RNA vaccine after two doses of CoronaVac vaccines against the Delta and Omicron variants.

OBJECTIVES: The study aimed to compare the immunogenicity and safety of fractional (half) third doses of heterologous COVID-19 vaccines (AZD1222 or BNT162b2) to full doses after the two-dose CoronaVac and when boosting after three different extended intervals. METHODS: At 60-<90, 90-<120, or 120-180 days intervals after the two-dose CoronaVac, participants were randomized to full-dose or half-dose AZD1222 or BNT162b2, followed up at day 28, 60, and 90. Vaccination-induced immune responses to Ancestral, Delta, and Omicron BA.1 strains were evaluated by antispike, pseudovirus, and microneutralization and T cell assays. Descriptive statistics and noninferiority cut-offs were reported as geometric mean concentration or titer and concentration or titer ratios comparing baseline to day 28 and day 90 and different intervals. RESULTS: No safety concerns were detected. All assays and intervals showed noninferior immunogenicity between full doses and half doses. However, full-dose vaccines and/or longer 120-180-day intervals substantially improved the immunogenicity (measured by antispike or measured by pseudotyped virus neutralizing titers 50; P <0.001). Seroconversion rates were over 90% against the SARS-CoV-2 strains by all assays. Immunogenicity waned more quickly with half doses than full doses but remained high against the Ancestral or Delta strains. Against Omicron, the day 28 immunogenicity increased with longer intervals than shorter intervals for full-dose vaccines. CONCLUSION: Immune responses after day 28 when boosting at longer intervals after the two-dose CoronaVac was optimal. Half doses met the noninferiority criteria compared with the full dose by all the immune assays assessed.

Social restriction versus herd immunity policies in the early phase of the SARS-CoV-2 pandemic: A mathematical modelling study.

BACKGROUND: Two main strategies to cope with the coronavirus disease 2019 (COVID-19) pandemic-lockdown (social restriction) and non-lockdown (herd immunity plan)-have been implemented in several countries. OBJECTIVE: This study aims to statistically compare the outcomes of the two strategies, represented by data from Thailand and Sweden, respectively. METHODS: Data for COVID-19 pandemic control from Thailand, representing social restriction, versus data from Sweden, representing the herd immunity plan, collected from January 13 to May 31, 2020, were analyzed by using the SIR (susceptible, infectious, recovered) model. RESULTS: The SIR model analysis demonstrated a beneficial effect of each model on the attenuation of the mortality rate, with lower mortality in social restriction and shorter overall pandemic duration in the herd immunity plan. However, the herd immunity plan demonstrated a higher mortality rate than social restriction (46.9% versus 1.9%) despite the later entry of the virus in Sweden. When the SIR model was used for predicting the COVID-19 status, Sweden was shown to likely end its COVID-19 epidemic earlier than Thailand (268 vs. 368 days). With the nonlinear estimation, at least one log difference between total confirmed cases versus active cases could be used as an indicator for relaxation of the lockdown policy in Thailand. CONCLUSIONS: Both the social restriction and herd immunity plans are beneficial for COVID-19 pandemic control in terms of the amelioration of pandemic mortality. The cumulative number of total recovered cases might be a potential parameter that could be used for determining the policy direction for COVID-19 control.

The Global Demand and Supply Balance of the Human Papillomavirus Vaccine: Implications for the Global Strategy for the Elimination of Cervical Cancer.

As of November 2023, 140 World Health Organization (WHO) member states had introduced human papillomavirus (HPV) vaccination in their routine immunization schedules. Despite a continuously increasing demand from countries across all income groups, supply constraints, COVID-19 pandemic disruptions, and other factors have slowed the pace of introduction, particularly in low-resource settings. Using a population-based forecasting methodology and leveraging the WHO's yearly vaccine supply data collection, we updated global demand and supply projections for the HPV vaccine for the period of 2022-2031. The analysis aimed at clarifying the magnitude of the challenges to bringing in equitable access to HPV vaccines, which can hinder the achievement of the Global Strategy for the Elimination of Cervical Cancer. The results of this analysis show that the risk of HPV shortages has significantly decreased, and global supply is now, under normal circumstances, sufficient to meet global demand. In the long term, HPV supply will be more than sufficient to meet the Global Strategy's goal of 90% of girls fully vaccinated with the HPV vaccine by the age of 15 years. Nonetheless, paying attention to the formulation of policies and carefully managing demand and supply will be required to ensure the long-term sustainability of the HPV vaccine program.

A phase III, multicenter, randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of catch-up vaccination regimens of V114, a 15-valent pneumococcal conjugate vaccine, in healthy infants, children, and adolescents (PNEU-PLAN).

BACKGROUND: Despite widespread use of pneumococcal conjugate vaccines (PCVs) in children, morbidity and mortality caused by pneumococcal disease (PD) remain high. In addition, many children do not complete their PCV course on schedule. V114 is a 15-valent PCV that contains two epidemiologically important serotypes, 22F and 33F, in addition to the 13 serotypes present in PCV13, the licensed 13-valent PCV. METHODS: This phase III descriptive study evaluated safety and immunogenicity of catch-up vaccination with V114 or PCV13 in healthy children 7 months-17 years of age who were either pneumococcal vaccine-naïve or previously immunized with lower valency PCVs (NCT03885934). Overall, 606 healthy children were randomized to receive V114 (n = 303) or PCV13 (n = 303) via age-appropriate catch-up vaccination schedules in three age cohorts (7-11 months, 12-23 months, or 2-17 years). RESULTS: Similar proportions of children 7-11 months and 2-17 years of age reported adverse events (AEs) in the V114 and PCV13 groups. A numerically greater proportion of children 12-23 months of age reported AEs in the V114 group (79.0%) than the PCV13 group (59.4%). The proportions of children who reported serious AEs varied between different age cohorts but were generally comparable between vaccination groups. No vaccine-related serious AEs were reported, and no deaths occurred. At 30 days after the last PCV dose, serotype-specific immunoglobulin G geometric mean concentrations were comparable between vaccination groups for the 13 shared serotypes and higher in the V114 group for 22F and 33F. CONCLUSIONS: Catch-up vaccination with V114 in healthy individuals 7 months-17 years of age was generally well tolerated and immunogenic for all 15 serotypes, including those not contained in PCV13, regardless of prior pneumococcal vaccination. These results support V114 catch-up vaccination in children with incomplete or no PCV immunization per the recommended schedule.

Antimicrobial Stewardship in Tropical Infectious Diseases: Focusing on Dengue and Malaria.

Acute undifferentiated febrile illness (AUFI) is the presenting symptom of various tropical and infectious diseases. Viral infection is generally the most common cause of AUFI, accounting for 8-11.8% of cases; thus, antibiotics might be unnecessary. Dengue and malaria are common tropical infectious diseases requiring effective supportive treatment and antimalarial agents, respectively. The uncertainty of early diagnosis results in widespread empirical antimicrobial treatment in high -income as well as in low-and middle-income countries. Although rapid diagnostic tests (RDTs) have been shown to limit antibiotic prescriptions in dengue and malaria, we observed a wide range of antibiotic prescriptions for 13-92.7% of cases in previous literature, particularly in RDT-negative malaria cases. Given several RDT limitations, antimicrobial stewardship (AMS) appears to be an effective strategy for controlling unnecessary antibiotic use and antimicrobial resistance (AMR) prevention. This program should be endorsed by a multidisciplinary team in tropical diseases to control collateral damage of inappropriate antimicrobial use. Empirical antibiotic treatment should be administered based on clinical judgement, microbiological evidence, and local epidemiological data. Rapid termination of antibiotic therapy, including disease control or elimination, is the mainstay of AMS in tropical diseases. Local and international sectors should implement an AMS programme to reduce AMR in the Tropics.

Adherence and Health Problems in Thai Travellers Living with HIV.

It is important to focus on adherence to antiretroviral therapy (ART) and health problems of travellers living with HIV (TLWHIV) during travel. This study was conducted to investigate factors related to adherence and health problems among TLWHIV. This multicentre, cross-sectional observational study was conducted among TLWHIV in university hospitals from August 2019 to July 2020. Factors associated with adherence to ART were evaluated using a logistic regression model. Health problems and risk exposure were also examined among participants during travel. Of 321 TLWHIV, 20 (6.23%) showed moderate-to-poor adherence, among whom 3 (15%) had viral rebound after travelling. Travellers frequently missed ART during the first 3 days of their trip. International destination was associated with moderate-to-poor adherence. In total, 237 (73.8%) travellers reported health problems during travel, among whom 36 required medical attention. Sexual or sharp exposure was found in <5% of travellers during travel. Approximately 95% of Thai TLWHIV had good ART adherence. International destination was the major factor determining adherence. TLWHIV should be encouraged to seek pretravel consultation. Healthcare providers should discuss health risk prevention and teach about ART dosing during travel to enhance adherence and minimise toxicity.

Factors associated with testing for HIV and other sexually transmitted infections in men who have sex with men and transgender women in Bangkok, Thailand.

BACKGROUND: Routine screening for HIV and other sexually transmitted infections (STIs) facilitates early diagnosis and treatment, thereby preventing morbidity and onward transmission. We estimated the prevalence of prior HIV/STI testing among men who have sex with men (MSM) and transgender women (TGW) in Bangkok, Thailand, and identified factors associated with prior testing. METHODS: Cross-sectional analyses were performed using data collected at enrollment into an HIV incidence cohort. From April to October 2017, MSM and TGW were enrolled if they were aged 18-35 years, reported anal intercourse with a male or TGW partner, and reported behavioral vulnerability to HIV. Participants answered questions about demographics, sexual behaviors, and lifetime HIV/STI testing history. Multivariable robust Poisson regression was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for factors potentially associated with prior testing. RESULTS: Among 1,014 participants, 348 (34.3%) were TGW and the median age was 21.6 (interquartile range 20.0-24.8) years. Prior testing for HIV was reported by 421 (41.5%) and for other STIs by 268 (26.4%). HIV testing was more common among participants aged ≥ 22 years (RR 1.37 [95% CI 1.13-1.67]), with college education as compared to secondary or less (RR 1.37 [95% CI 1.08-1.72]), and who met male sexual partners online (RR 1.52 [95% CI 1.24-1.85]), but lower among participants attracted to both men and women as compared to men only (RR 0.64 [95% CI 0.51-0.81]) and who met male sexual partners in bars (RR 0.83 [95% CI 0.72-0.97]). Similar associations were observed with prior testing for other STIs, including increased testing among participants with college education (RR 1.52 [95% CI 1.11-2.09]) and who met male sexual partners online (RR 1.73 [95% CI 1.30-2.31]), but lower among participants attracted to both men and women (RR 0.70 [95% CI 0.51-0.96]) and who met male sexual partners in bars (RR 0.67 [95% CI 0.54-0.83]). CONCLUSIONS: Despite behavioral vulnerability, prior testing for HIV and other STIs was uncommon. Online engagement strategies may be effectively reaching Thai MSM and TGW who meet sexual partners online, but new interventions are needed to encourage testing among younger, less educated, and bisexual MSM and TGW.

Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomised, placebo-controlled, phase 1 trial.

Background: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It's being developed by public sector manufacturers in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. Methods: This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy males and non-pregnant females, aged 18-59 years and negative for SARS-CoV-2 antibodies, were eligible. Participants were randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 µg, 1 µg+CpG1018 (a toll-like receptor 9 agonist), 3 µg, 3 µg+CpG1018, 10 µg, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422). Findings: Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enroled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5·7% to 17·1% among vaccine groups and was 2·9% in controls; there was no vaccine-related serious adverse event. The 10 µg formulation's immunogenicity ranked best, followed by 3 µg+CpG1018, 3 µg, 1 µg+CpG1018, and 1 µg formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122·23 international units per mL (IU/mL; 1 µg, 95% confidence interval (CI) 86·40-172·91) to 474·35 IU/mL (10 µg, 95% CI 320·90-701·19), with 93·9% to 100% of vaccine groups attaining a ≥ 4-fold increase over baseline. Interpretation: NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 µg and 3 µg+CpG1018 formulations advanced to phase 2. Funding: National Vaccine Institute (Thailand), National Research Council (Thailand), Bill & Melinda Gates Foundation, National Institutes of Health (USA).

A Quantitative Approach to Unravel the Role of Host Genetics in IgG-FcγR Complex Formation After Vaccination.

Fc-mediated immune functions have been correlated with protection in the RV144 HIV vaccine trial and are important for immunity to a range of pathogens. IgG antibodies (Abs) that form complexes with Fc receptors (FcRs) on innate immune cells can activate Fc-mediated immune functions. Genetic variation in both IgGs and FcRs have the capacity to alter IgG-FcR complex formation via changes in binding affinity and concentration. A growing challenge lies in unraveling the importance of multiple variations, especially in the context of vaccine trials that are conducted in homogenous genetic populations. Here we use an ordinary differential equation model to quantitatively assess how IgG1 allotypes and FcγR polymorphisms influence IgG-FcγRIIIa complex formation in vaccine-relevant settings. Using data from the RV144 HIV vaccine trial, we map the landscape of IgG-FcγRIIIa complex formation predicted post-vaccination for three different IgG1 allotypes and two different FcγRIIIa polymorphisms. Overall, the model illustrates how specific vaccine interventions could be applied to maximize IgG-FcγRIIIa complex formation in different genetic backgrounds. Individuals with the G1m1,17 and G1m1,3 allotypes were predicted to be more responsive to vaccine adjuvant strategies that increase antibody FcγRIIIa affinity (e.g. glycosylation modifications), compared to the G1m-1,3 allotype which was predicted to be more responsive to vaccine boosting regimens that increase IgG1 antibody titers (concentration). Finally, simulations in mixed-allotype populations suggest that the benefit of boosting IgG1 concentration versus IgG1 affinity may be dependent upon the presence of the G1m-1,3 allotype. Overall this work provides a quantitative tool for rationally improving Fc-mediated functions after vaccination that may be important for assessing vaccine trial results in the context of under-represented genetic populations.

Long-term effectiveness of human papillomavirus vaccines among adult women: A real-world scenario.

OBJECTIVE: This study aimed to determine the real-world effectiveness of bi- or quadrivalent human papillomavirus (HPV) vaccines in Thai adult women ≥5 years post-vaccination in reducing HPV 16/18-associated low-grade squamous intraepithelial lesions or worse (LSIL+), atypical squamous cells of undetermined significance or worse (ASC-US+), and HPV 16/18 positivity. METHODS: A retrospective cohort study was conducted among Thai women aged 20-45 years in Bangkok. The vaccinated and unvaccinated groups were matched according to baseline years. HPV/Pap test results were collected from the medical records and/or obtained by cervical sample collection at the study sites. Adjusted hazard ratios were measured using multivariable Cox regression analyses. RESULTS: A total of 993 participants (493 vaccinated and 500 unvaccinated) were enrolled from 2018 to 2019. The median ages at baseline of the vaccinated and unvaccinated groups were 33 years (interquartile range [IQR] 27-38) and 34 years (IQR 30-38), respectively. The median follow-up periods were 7.3 years (IQR 6.1-8.6) and 7.2 years (IQR 5.8-8.9) for the vaccinated group and the unvaccinated group, respectively. More women in the vaccinated group were single (29.2% vs. 13.2%, P < 0.001) and university graduates (83.2% vs. 75.4%, P = 0.009). The vaccinated and unvaccinated groups had similar personal monthly incomes (>20,000 THB/month, 63.9% vs. 62.4%, respectively, P = 0.685). There were no cases of HPV 16/18-associated LSIL+ in the vaccinated group, whereas there were four cases in the unvaccinated group. HPV vaccine effectiveness was 88.0% (95% CI 2.0-98.5) in the reduction of HPV 16/18-associated ASC-US+, and 84.6% (95% CI 43.5-95.8) in the reduction of HPV 16/18 positivity. CONCLUSIONS: HPV vaccine effectiveness was high in adult women in a real-world scenario in a developing country. Free HPV vaccination in adult women in this age group should be further explored when vaccine supplies are not limited. (HPV: human papillomavirus. LSIL+: low-grade squamous intraepithelial lesion or worse. ASC-US+: atypical squamous cells of undetermined significance or worse).

Systematic comparison of HIV-1 Envelope-specific IgG responses induced by different vaccination regimens: Can we steer IgG recognition towards regions of viral vulnerability?

Immunogens and vaccination regimens can influence patterns of immune-epitope recognition, steering them towards or away from epitopes of potential viral vulnerability. HIV-1 envelope (Env)-specific antibodies targeting variable region 2 (V2) or 3 (V3) correlated with protection during the RV144 trial, however, it was suggested that the immunodominant V3 region might divert antibody responses away from other relevant sites. We mapped IgG responses against linear Env epitopes in five clinical HIV vaccine trials, revealing a specific pattern of Env targeting for each regimen. Notable V2 responses were only induced in trials administering CRF01_AE based immunogens, but targeting of V3 was seen in all trials, with the soluble, trimeric CN54gp140 protein eliciting robust V3 recognition. Strong V3 targeting was linked to greater overall response, increased number of total recognised antigenic regions, and where present, stronger V2 recognition. Hence, strong induction of V3-specific antibodies did not negatively impact the targeting of other linear epitopes in this study, suggesting that the induction of antibodies against V3 and other regions of potential viral vulnerability need not be necessarily mutually exclusive.