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Introduction: The HVTN 105 vaccine clinical trial tested four combinations of two immunogens - the DNA vaccine DNA-HIV-PT123, and the protein vaccine AIDSVAX B/E. All combinations induced substantial antibody and CD4+ T cell responses in many participants. We have now re-examined the intracellular cytokine staining flow cytometry data using the high-resolution SWIFT clustering algorithm, which is very effective for enumerating rare populations such as antigen-responsive T cells, and also determined correlations between the antibody and T cell responses. Methods: Flow cytometry samples across all the analysis batches were registered using the swiftReg registration tool, which reduces batch variation without compromising biological variation. Registered data were clustered using the SWIFT algorithm, and cluster template competition was used to identify clusters of antigen-responsive T cells and to separate these from constitutive cytokine producing cell clusters. Results: Registration strongly reduced batch variation among batches analyzed across several months. This in-depth clustering analysis identified a greater proportion of responders than the original analysis. A subset of antigen-responsive clusters producing IL-21 was identified. The cytokine patterns in each vaccine group were related to the type of vaccine -- protein antigens tended to induce more cells producing IL-2 but not IFN-g, whereas DNA vaccines tended to induce more IL-2+ IFN-g+ CD4 T cells. Several significant correlations were identified between specific antibody responses and antigen-responsive T cell clusters. The best correlations were not necessarily observed with the strongest antibody or T cell responses. Conclusion: In the complex HVTN105 dataset, alternative analysis methods increased sensitivity of the detection of antigen-specific T cells; increased the number of identified vaccine responders; identified a small IL-21-producing T cell population; and demonstrated significant correlations between specific T cell populations and serum antibody responses. Multiple analysis strategies may be valuable for extracting the most information from large, complex studies. [ABSTRACT FROM AUTHOR]

IntroductionThe HVTN 105 vaccine clinical trial tested four combinations of two immunogens - the DNA vaccine DNA-HIV-PT123, and the protein vaccine AIDSVAX B/E. All combinations induced substantial antibody and CD4+ T cell responses in many participants. We have now re-examined the intracellular cytokine staining flow cytometry data using the high-resolution SWIFT clustering algorithm, which is very effective for enumerating rare populations such as antigen-responsive T cells, and also determined correlations between the antibody and T cell responses.MethodsFlow cytometry samples across all the analysis batches were registered using the swiftReg registration tool, which reduces batch variation without compromising biological variation. Registered data were clustered using the SWIFT algorithm, and cluster template competition was used to identify clusters of antigen-responsive T cells and to separate these from constitutive cytokine producing cell clusters.ResultsRegistration strongly reduced batch variation among batches analyzed across several months. This in-depth clustering analysis identified a greater proportion of responders than the original analysis. A subset of antigen-responsive clusters producing IL-21 was identified. The cytokine patterns in each vaccine group were related to the type of vaccine – protein antigens tended to induce more cells producing IL-2 but not IFN-γ, whereas DNA vaccines tended to induce more IL-2+ IFN-γ+ CD4 T cells. Several significant correlations were identified between specific antibody responses and antigen-responsive T cell clusters. The best correlations were not necessarily observed with the strongest antibody or T cell responses.ConclusionIn the complex HVTN105 dataset, alternative analysis methods increased sensitivity of the detection of antigen-specific T cells; increased the number of identified vaccine responders; identified a small IL-21-producing T cell population; and demonstrated significant correlations between specific T cell populations and serum antibody responses. Multiple analysis strategies may be valuable for extracting the most information from large, complex studies.

Conducting a vaccine trial in a low- and middle-income country (LMIC) can present unique challenges and lessons learned. This Ebola vaccine trial, enrolling 699 healthcare providers and frontliners and jointly set up by the University of Antwerp (Sponsor) and the University of Kinshasa (Principal Investigator (PI)), was conducted in Boende, a remote city in the Democratic Republic of the Congo (DRC), between December 2019 and October 2022 (ClinicalTrials.gov : NCT04186000). While being bound by strict ICH-GCP and international funder regulations, this trial, exemplary for being a public–private partnership, required collaboration between several international stakeholders (e.g., two universities, a pharmaceutical company, and a clinical research organization), local communities and government agencies. Here we address several logistical and administrative challenges, cultural differences, language barriers and regulatory, political, and ethical considerations over the trial's 2.5-year duration, while tailoring and adapting the study to the specific local context. Lessons learned include the importance of clear communication with participants in all phases of the study, but also within the study team and among different stakeholders. Challenges, mitigations, and lessons learned are presented in nine categories (e.g., safety management; trial documentation, tools, and materials; communication, staff training and community engagement/sensitization; financial and administrative hurdles; and more). Ultimately, to reach the successful end of the vaccine trial in this remote Ebola endemic area in the DRC, careful planning, collaboration, and great flexibility and adaptability was often required from all involved partners. Despite the encountered challenges, the vaccine trial discussed in this paper was able to obtain high participant retention rates (i.e., 92% of participants completed the study). We hope that other international teams aspiring to conduct similar trials in remote areas of LMICs can learn from the way our challenges were addressed, mitigations developed, and lessons were learned. [ABSTRACT FROM AUTHOR]

The inconsistent European vaccine trial landscape rendered the continent of limited interest for vaccine developers. The VACCELERATE consortium created a network of capable clinical trial sites throughout Europe. VACCELERATE identifies and provides access to state-of-the-art vaccine trial sites to accelerate clinical development of vaccines. Login details for the VACCELERATE Site Network (vaccelerate.eu/site-network/) questionnaire can be obtained after sending an email to. Interested sites provide basic information, such as contact details, affiliation with infectious disease networks, main area of expertise, previous vaccine trial experience, site infrastructure and preferred vaccine trial settings. In addition, sites can recommend other clinical researchers for registration in the network. If directly requested by a sponsor or sponsor representative, the VACCELERATE Site Network pre-selects vaccine trial sites and shares basic study characteristics provided by the sponsor. Interested sites provide feedback with short surveys and feasibility questionnaires developed by VACCELERATE and are connected with the sponsor to initiate the site selection process. As of April 2023, 481 sites from 39 European countries have registered in the VACCELERATE Site Network. Of these, 137 (28.5 %) sites have previous experience conducting phase I trials, 259 (53.8 %) with phase II, 340 (70.7 %) with phase III, and 205 (42.6 %) with phase IV trials, respectively. Infectious diseases were reported as main area of expertise by 274 sites (57.0 %), followed by any kind of immunosuppression by 141 (29.3 %) sites. Numbers are super additive as sites may report clinical trial experience in several indications. Two hundred and thirty-one (47.0 %) sites have the expertise and capacity to enrol paediatric populations and 391 (79.6 %) adult populations. Since its launch in October 2020, the VACCELERATE Site Network has been used 21 times for academic and industry trials, mostly interventional studies, focusing on different pathogens such as fungi, monkeypox virus, Orthomyxoviridae /influenza viruses, SARS-CoV-2, or Streptococcus pneumoniae /pneumococcus. The VACCELERATE Site Network enables a constantly updated Europe-wide mapping of experienced clinical sites interested in executing vaccine trials. The network is already in use as a rapid-turnaround single contact point for the identification of vaccine trials sites in Europe. [ABSTRACT FROM AUTHOR]

Background: Outbreaks of Marburg virus disease (MVD) are rare and small in size, with only 18 recorded outbreaks since 1967, only two of which involved more than 100 cases. It has been proposed, therefore, that Phase 3 trials for MVD vaccines should be held open over multiple outbreaks until sufficient end points accrue to enable vaccine efficacy (VE) to be calculated. Here we estimate how many outbreaks might be needed for VE to be estimated. Methods: We adapt a mathematical model of MVD transmission to simulate a Phase 3 individually randomised placebo controlled vaccine trial. We assume in the base case that vaccine efficacy is 70% and that 50% of individuals in affected areas are enrolled into the trial (1:1 randomisation). We further assume that the vaccine trial starts two weeks after public health interventions are put in place and that cases occurring within 10 days of vaccination are not included in VE calculations. Results: The median size of simulated outbreaks was 2 cases. Only 0.3% of simulated outbreaks were predicted to have more than 100 MVD cases. 95% of simulated outbreaks terminated before cases accrued in the placebo and vaccine arms. Therefore the number of outbreaks required to estimate VE was large: after 100 outbreaks, the estimated VE was 69% but with considerable uncertainty (95% CIs: 0%−100%) while the estimated VE after 200 outbreaks was 67% (95% CIs: 42%−85%). Altering base-case assumptions made little difference to the findings. In a sensitivity analysis, increasing R0 by 25% and 50% led to an estimated VE after 200 outbreaks of 69% (95% CIs: 53–85%) and 70% (95% CIs: 59–82%), respectively. Conclusions: It is unlikely that the efficacy of any candidate vaccine can be calculated before more MVD outbreaks have occurred than have been recorded to date. This is because MVD outbreaks tend to be small, public health interventions have been historically effective at reducing transmission, and vaccine trials are only likely to start after these interventions are already in place. Hence, it is expected that outbreaks will terminate before, or shortly after, cases start to accrue in the vaccine and placebo arms.

Future efficacy testing of interventions to prevent HIV or other infections will require engagement of vulnerable populations. We characterized willingness to participate in a future HIV vaccine trial and barriers to participation among men who have sex with men in a 12-month German cohort study. Among 1015 participants at enrollment, 604 (60%) reported willingness, 60 (6%) were unwilling, 351 (35%) were unsure or refused to answer. Among those unwilling, the primary reason was fear of getting HIV. Among those willing, reasons included protection against HIV and furthering scientific knowledge. In a multivariable logistic regression model, higher odds of willingness to participate were seen among participants at the 12-month visit (aOR: 1.09, 95% CI: 1.04–1.15) and with prior knowledge of HIV vaccine research (aOR: 1.14, 95% CI: 1.06–1.23). Educating potential participants about vaccine research may facilitate recruitment and participation in future trials of HIV vaccine candidates and other prevention interventions.

Introduction: The WHO currently recommends giving pneumococcal conjugate vaccines (PCVs) as three doses – either three doses in infancy with Pentavalent vaccine (3p+0), or two doses in infancy followed by a booster around 12 months (2p+1). However, their high price is a barrier to introduction and sustainability in low and middle-income countries. We hypothesize that a schedule with a single priming and a booster dose (1p+1) may maintain similar levels of protection for the community by sustaining herd immunity, once circulation of vaccine types has been controlled. Methods and analysis: We will conduct a cluster randomized trial with four intervention arms (1p+1, 0p+1, 2p+1, 3p+0) and three unvaccinated clusters in the 27 communes of Nha Trang, central Vietnam. A PCV catch-up vaccination campaign to all children under three years of age will be performed at the start of the trial. The primary endpoint is non-inferiority of the1p+1 schedule if compared to the WHO standard 2p+1 and 3p+0 schedules in reducing vaccine serotype carriage prevalence in infants. We will also explore impact of 0p+1 schedule. A baseline and annual pneumococcal carriage surveys of 6480 participants per survey covering infants, toddlers and their mothers will be conducted. Ethics and dissemination: Ethical approvals were obtained from the ethical review committees of Institute of Tropical Medicine, Nagasaki University (151203149-2) and the Ministry of Health, Vietnam (1915/QD-BYT). The results, interpretation and conclusions will be presented at national and international conferences, and published in peer-reviewed open access journals. Trial registration number: NCT02961231

Globally, >80 million new gonorrhea infections occur annually. Here, we assessed barriers to and influences on participation in a gonorrhea clinical trial and the impact of educational intervention. The survey was fielded in the US in March 2022. Higher enrollment of Black/African Americans and younger individuals than represented in the US demographic distribution reflected the higher incidence of gonorrhea in these groups. Behavioral characteristics and baseline attitudes toward vaccination were collected. Participants were probed on their knowledge of and likelihood to enroll in general and gonorrhea vaccine trials. Participants hesitant to enroll in a gonorrhea vaccine trial were given nine bullets of basic facts about the disease and asked again to rank their likelihood to enroll. Overall, 450 individuals completed the survey. Fewer participants were willing (quite/very likely) to join a gonorrhea versus a general vaccine trial (38.2% [172/450] vs. 57.8% [260/450]). The likelihood to enroll in any vaccine trial or a gonorrhea vaccine trial was greater with higher self-declared knowledge (Spearman's ρ = 0.277 [p < 0.001] and 0.316 [p < 0.001], respectively) and baseline openness towards vaccination (p < 0.001 for both). Self-declared awareness of gonorrhea was associated with age (p = 0.001), education (p = 0.031), and ethnicity/race (p = 0.002), with older, more educated, and Black/African Americans having higher awareness. Males (p = 0.001) and those with more sexual partners (p < 0.001) were more likely to enroll in a gonorrhea vaccine trial. Educational intervention had a significant (p < 0.001) impact on hesitancy. Improvement in willingness to enroll in a gonorrhea vaccine trial was greatest in those initially marginally hesitant and lowest in those initially strongly hesitant. Basic educational intervention has the potential to improve recruitment into gonorrhea vaccine trials. [ABSTRACT FROM AUTHOR]

This article explores the idea of relationality and distributive agency in the context of a clinical vaccine trial. The diarrhoea vaccine trial was conducted in Finnish adults, who travelled to West Africa1. Engaging with previous research on clinical trials in the global South that has emphasized the relationality and social embeddedness of Southern trial subjects, this article argues for an enacted social-material relationality of any research subject. As the vaccine trial under study transformed into practices and ideas of helping, the analysis illustrates forms of relational subjectivity and distributive agency by focusing on the notion of helping. The analysis is based on the trial participants' accounts and practices, and draws on qualitative interviews (51) and ethnographic observation conducted between 2017 and 2019 at the trial site in West Africa. [ABSTRACT FROM AUTHOR]

In early 2020, adult volunteers were invited to participate in a first-in-human trial of the COVID-19 vaccine, ChAdOx1 nCoV-19, in the United Kingdom (UK) at the height of the global pandemic when there was uncertainty regarding vaccine efficacy and side-effects. We conducted a retrospective survey of these uniquely situated individuals to gain insight into their views about the risks, motivations, and expectations of the trial and potential vaccine deployment. Our data from 349 respondents show that these volunteers were educated to a high-level with a clear understanding of the seriousness of the COVID-19 pandemic, as well as an appreciation of the role of science and research in developing a vaccine to address this global problem. Individuals were primarily motivated with altruistic intent and expressed a desire to contribute to the scientific effort. Respondents appreciated that their participation was associated with risk but appeared comfortable that this risk was low. Through our analysis, we highlight these individuals as a group with strong levels of trust in science and a sense of societal responsibility, and therefore are a potential valuable resource to improve confidence in novel vaccines. Vaccine trial participants could offer a credible collective voice to support positive messaging around vaccination.

Background: The media have played an important part in presenting arguments for and against vaccination. The potential for the media to influence public attitudes to vaccines is becoming increasingly crucial to address., Methods: To understand the differing roles and responsibilities in the communication of vaccine trials we draw insight from a retrospective study of 349 survey responses and 102 semi-structured interviews conducted in 2020 with participants in the United Kingdom's first-in-human clinical trial of the Oxford-AstraZeneca COVID-19 vaccine., Results: We found that trial participants had mixed views as to whether their participation conferred responsibility to communicate more widely about their trial experiences. Some participants perceived themselves to have an altruistic obligation to communicate to the media about the trial, and others felt that those who did share their participation had 'attention-seeking' motives. When participants did speak out they preferred to do so anonymously. Frustration was also reported with sensationalised and false media stories. Social media was viewed as a means to accelerate misinformation or as a force for recruitment and public education about trials. Participants were pleased to see trial investigators and trial team playing prominent roles in the media and this instilled confidence in the vaccine and the trial. We discuss these evolving roles and responsibilities for trial communication, concentrating on the views of participants about experiences, opportunities, and risks., Conclusions: We argue that the pandemic has demonstrated the need for clinical trials to be made more transparent as a scientific practice that requires better public understanding and engagement. For high-profile vaccine trials we recommend; (1) explicit and comprehensive guidance aimed at all participants for interactions with the media; (2) prioritising having open and effectively expressed accounts of trial composition, processes, and participation; (3) offering support and a direct communication channel for journalists to report trials by utilising internal press officers to engage with journalists., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors except SV have worked or are currently working on the UK clinical trials of the SARS-COV-2 candidate vaccine; ChAdOx1 nCoV-19. AJP is the chief investigator of these clinical trials., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This research aims to understand the level and determinants of people’s willingness to participate in a vaccine trial for COVID-19 in Senegal. We conducted a telephone survey among a marginal quota sample of 607 people over 18 years of age. Only 44.3% of the participants wanted to participate in a vaccine trial for COVID-19, with females intending to participate more than males (AOR = 1.82, 95% CI [1.22–2.72]). Participants who intended to be vaccinated against COVID-19 (AOR = 6.48, 95% CI [4.12–10.4]) and who thought that being infected with the coronavirus would have a significant impact on their health (AOR = 2.34, 95% CI [1.57, 3.51]) were more likely to agree to take part in the COVID-19 vaccine trial. Confidence in the vaccine, health personnel, and the government in the fight against the pandemic are key factors in participants’ willingness to participate in a vaccine trial in Senegal.

According to the World Health Organization, the American region has the highest coronavirus disease-2019 (COVID-19) cases and deaths since the start of the pandemic. This humanitarian tragedy presented the possibility of generating efficacy data from COVID-19 vaccine trials. The race to develop successful vaccines imposed a high demand for trained healthcare personnel and clinical sites where large scale randomized clinical trials could be conducted. This site readiness initiative, funded by the Bill and Melinda GatesFoundation (BMGF), was carried out to rapidly build site capacity for running COVID-19 vaccine trials in Latin America.Twenty-two sites across 7 countries were selected and received funding. Site selection was based on defined feasibility criteria which deemed these sites as suitable for running vaccine efficacy trials. Criteria for selection included investigator and core permanent staff experience, public health measures in place for COVID-19, import/export requirements for study drug and biological specimens, a clear and accelerated ethical and regulatory approval process for COVID-19 trials. Training was tailored and delivered according to the experience level of the investigator and site staff, and included GCP training, standard operating procedures (SOP) fundamentals, conducting vaccine trials, COVID-19 pathophysiology, and vaccine trials lessons learned. Most of the grant funds were utilized for space expansion and renovation (46 %) followed by purchase of equipment (36 %); the remaining 18 % was spent on human resources. By the end of this site readiness initiative project, which took approximately 4 months, 21 of 22 (95 %) sites had agreements in place or were in discussions with sponsors to conduct large scale COVID-19 vaccine trials.

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Clinical trials are complicated, time-consuming and costly. From the initial screening, informed consent and recruitment of the participants’ to study completion, the sponsor must undertake a wide array of complex and closely monitored operations, complying with international standards for human subject research and local requirements. Conducting these studies in an underdeveloped country, with limited resources, infrastructure, and experience with regulated clinical trials adds to this complexity. The initial site selection, set up and preparatory activities for the clinical trial are crucial to minimizing the risks to both participants and to successful completion during the subsequent study execution. In this paper, we describe the experience and lessons learned of building clinical trial site capacity in terms of infrastructure and human resource development for a Phase III vaccine clinical trial. We believe that sharing the experience of setting up a clinical trial in a resource-limited country will enable other entities contemplating clinical research in these countries, to prepare and plan ahead, to minimize the impact of barriers, and to contribute to bringing more studies to the countries where people live with the burden of vaccine-preventable, poverty-associated diseases.

• Clinical trial regulations are becoming increasingly complex and demanding for low- and middle-income countries (LMICs) • International collaboration based on equal partnership can help LMICs perform high quality vaccine trials. • Maintaining acquired capacity while conducting clinical trials in LMICs is key and needs long term international support. • Transparency of lessons learned during clinical trials can assist for a more efficient conduct of trials. • This article describes the challenges, mitigations and lessons learned during the setup of a vaccine trial in a LMIC. Since the largest Ebola outbreak in West Africa (2013–2016) highlighted the potential threat of the Ebola virus to the world, several vaccines have been under development by different pharmaceutical companies. To obtain vaccine licensure, vaccine trials assessing the safety, immunogenicity and efficacy of new vaccines among different populations (e.g. different in age, gender, race, and ethnicity) play a crucial role. However, while this deadly disease mainly affects Central and West Africa, clinical trial regulations are becoming increasingly complex and consequently more expensive, influencing the affected low- and middle-income countries (LMICs) in performing high quality clinical trials. Consequently, the completion of such trials in LMICs takes more time and vaccines and drugs take longer to be licensed. To overcome some of the obstacles faced, the EBOVAC3 consortium, funded by the European Union's Innovative Medicines Initiative and the Coalition for Epidemic Preparedness Innovations, enabled high quality vaccine trials in Central and West Africa through extensive North-South collaborations. In this article, the encountered challenges, mitigations, recommendations and lessons learned from setting-up an Ebola vaccine trial in a remote area of the Democratic Republic of Congo are presented. These challenges are grouped into eight categories: (1) Regulatory, political and ethical, (2) Trial documents, (3) International collaborations, (4) Local trial staff, (5) Community engagement and sensitization, (6) Logistics, (7) Remoteness and climate conditions, (8) Financial. By sharing the encountered challenges, implemented mitigations and lessons learned for each of these categories, we hope to prepare and inform other researchers aspiring a well-functioning clinical trial unit in similar remote settings in LMICs. ClinicalTrials.gov identifier: NCT04186000. [ABSTRACT FROM AUTHOR]

Abstract Background RTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009–2014 phase III trial (MALARIA-055, NCT00866619 ), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted. Methods We implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6–12 weeks) and children (5–17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation. Results Vaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner. Conclusions Vegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called “dambos” which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context. Trial registration Efficacy of GSK Biologicals’ Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009.

Globally, >80 million new gonorrhea infections occur annually. Here, we assessed barriers to and influences on participation in a gonorrhea clinical trial and the impact of educational intervention. The survey was fielded in the US in March 2022. Higher enrollment of Black/African Americans and younger individuals than represented in the US demographic distribution reflected the higher incidence of gonorrhea in these groups. Behavioral characteristics and baseline attitudes toward vaccination were collected. Participants were probed on their knowledge of and likelihood to enroll in general and gonorrhea vaccine trials. Participants hesitant to enroll in a gonorrhea vaccine trial were given nine bullets of basic facts about the disease and asked again to rank their likelihood to enroll. Overall, 450 individuals completed the survey. Fewer participants were willing (quite/very likely) to join a gonorrhea versus a general vaccine trial (38.2% [172/450] vs. 57.8% [260/450]). The likelihood to enroll in any vaccine trial or a gonorrhea vaccine trial was greater with higher self-declared knowledge (Spearman’s ρ = 0.277 [p < 0.001] and 0.316 [p < 0.001], respectively) and baseline openness towards vaccination (p < 0.001 for both). Self-declared awareness of gonorrhea was associated with age (p = 0.001), education (p = 0.031), and ethnicity/race (p = 0.002), with older, more educated, and Black/African Americans having higher awareness. Males (p = 0.001) and those with more sexual partners (p < 0.001) were more likely to enroll in a gonorrhea vaccine trial. Educational intervention had a significant (p < 0.001) impact on hesitancy. Improvement in willingness to enroll in a gonorrhea vaccine trial was greatest in those initially marginally hesitant and lowest in those initially strongly hesitant. Basic educational intervention has the potential to improve recruitment into gonorrhea vaccine trials.

In 1804, Cuban physician Tomás Romay tried and failed to create the first yellow fever vaccine. The article analyzes his experimental efforts, foregrounding the enslaved and enlisted subjects at the center of this early vaccine trial. Though a scientific failure, this brief experiment, the desires and logics embedded within it, and the measures deployed in its wake - in the form of European whitening campaigns - allow us to consider the political uses of immunity during the Age of Atlantic Revolutions. Historicizing these events within the wider geopolitics of the Caribbean, the article explicates the central role that yellow fever immunization played in Cuban authorities' attempts to shore up their political and economic sovereignty in the midst of anti-colonial and anti-slavery resistance. As such, it shows how yellow fever and its threat to social and economic order fits within a broader history of vaccination as a mechanism of colonial governance. Finally, by situating Cuban efforts to prevent yellow fever alongside the health concerns of enslaved people - concerns that arguably informed their resistance to slavery - the article also demonstrates how ideas about immunity and political belonging increasingly intersected through whiteness as an elite ideal in the era that Cuba first became a slave society., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Immune response decays over time, and vaccine-induced protection often wanes. Understanding how vaccine efficacy changes over time is critical to guiding the development and application of vaccines in preventing infectious diseases. The objective of this article is to develop statistical methods that assess the effect of decaying immune responses on the risk of disease and on vaccine efficacy, within the context of Cox regression with sparse sampling of immune responses, in a baseline-naive population. We aim to further disentangle the various aspects of the time-varying vaccine effect, whether direct on disease or mediated through immune responses. Based on time-to-event data from a vaccine efficacy trial and sparse sampling of longitudinal immune responses, we propose a weighted estimated induced likelihood approach that models the longitudinal immune response trajectory and the time to event separately. This approach assesses the effects of the decaying immune response, the peak immune response, and/or the waning vaccine effect on the risk of disease. The proposed method is applicable not only to standard randomized trial designs but also to augmented vaccine trial designs that re-vaccinate uninfected placebo recipients at the end of the standard trial period. We conducted simulation studies to evaluate the performance of our method and applied the method to analyze immune correlates from a phase III SARS-CoV-2 vaccine trial., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. [br]For permissions, please e-mail: journals.permissions@oup.com.)

• Globally, 1.5 million cases of Hepatitis A virus infection are reported each year. • Numerous outbreaks of Hepatitis A virus infection were reported in India. • This study compared the safety and immunogenicity of HAPIBEV™ with Havrix®720. • HAPIBEV™ showed non-inferiority compared to Havrix®. • The safety profile was comparable between both vaccines. The Biological E inactivated hepatitis A (HAPIBEV™) vaccine was developed by importing the Healive® vaccine bulk from China and fill-finish it in India. Healive® vaccine is approved in China for both children and adults. This study assessed the safety and immunogenicity of HAPIBEV™ vaccine as compared to the Havrix 720® vaccine of GlaxoSmithKline (GSK) pharmaceuticals when administered intramuscularly (IM) 6 months apart in 1–15 years old hepatitis A virus (HAV) vaccine naive children in India. This Phase 3, single blind, parallel, randomized, active-controlled, two-arm study was conducted at 8 centers in India in healthy HAV vaccine–naive children. Subjects were stratified into 2 age subsets (1–7 and 8–15 years) and randomly assigned to either BE-HAPIBEV™ or GSK's Havrix® vaccine and administered 2 IM injections 6 months apart. The immunogenicity evaluations included: (1) proportion of subjects who achieved the following at Day 210 from baseline: (a) seroconversion (≥20 mIU/mL) with anti-HAV immunoglobulin G (IgG) antibodies, (b) ≥4-fold increase in anti-HAV IgG antibodies, and (c) ≥2-fold increase in anti-HAV IgG antibodies concentration who were already seroconverted at baseline and (2) geometric mean concentrations (GMC) of anti-HAV IgG antibodies at baseline and Day 210. Safety was evaluated throughout the study. A total of 467 (89.8%) subjects completed the study. The non-inferiority criterion was met by HAPIBEV™ vaccine as seroconversion rates in both vaccine groups were 100%. Overall, other immunogenicity evaluations were either similar in both vaccine groups or higher in the HAPIBEV™ group compared with the Havrix® group. The safety profile was also comparable between HAPIBEV™ and Havrix® groups. The most common adverse event (AE) was injection site pain, and the majority of AEs were mild in severity. The HAPIBEV™ vaccine demonstrated an immunological and safety profile on par with Havrix® in 1–15 years old healthy HAV vaccine-naive Indian children. This study is registered with clinical trial registry of India bearing no: CTRI/2019/04/018384 on 02 Apr 2019. [ABSTRACT FROM AUTHOR]

Nipah virus (NiV) is an emerging, bat-borne pathogen that can be transmitted from person-to-person. Vaccines are currently being developed for NiV, and studies have been funded to evaluate their safety and immunogenicity. An important unanswered question is whether it will be possible to evaluate the efficacy of vaccine candidates in phase III clinical trials in a context where spillovers from the zoonotic reservoir are infrequent and associated with small outbreaks. The objective of this study was to investigate the feasibility of conducting a phase III vaccine trial in Bangladesh, the only country regularly reporting NiV cases. We used simulations based on previously observed NiV cases from Bangladesh, an assumed vaccine efficacy of 90% and other NiV vaccine target characteristics, to compare three vaccination study designs: (i) cluster randomized ring vaccination, (ii) cluster randomized mass vaccination, and (iii) an observational case-control study design. The simulations showed that, assuming a ramp-up period of 10 days and a mean hospitalization delay of 4 days,a cluster-randomized ring vaccination trial would require 516 years and over 163,000 vaccine doses to run a ring vaccination trial under current epidemic conditions. A cluster-randomized mass vaccination trial in the two most affected districts would take 43 years and 1.83 million vaccine doses. An observational case-control design in these two districts would require seven years and 2.5 million vaccine doses. Without a change in the epidemiology of NiV, ring vaccination or mass vaccination trials are unlikely to be completed within a reasonable time window. In this light, the remaining options are: (i) not conducting a phase III trial until the epidemiology of NiV changes, (ii) identifying alternative ways to licensure such as observational studies or controlled studies in animals such as in the US Food and Drug Administration's (FDA) Animal Rule. [ABSTRACT FROM AUTHOR]

Despite the important benefits of maternal vaccination for pregnant women and newborns, vaccination uptake is low in many European countries. Differences in vaccination policies and recommendations, as well as concerns about vaccine safety can partly explain inadequate coverage rates and women's hesitancy to get vaccinated during pregnancy. This study aims to explore pregnant women's experiences, decision-making processes and perceptions towards maternal vaccination and maternal vaccine trials in France, Germany, Italy, Spain and the United Kingdom. Qualitative interviews and focus groups were conducted with 258 pregnant women identified through local research panels and snowballing. Topic guides translated in local languages were designed to explore women's awareness and perceptions of maternal vaccination, and willingness to participate in vaccine trials during pregnancy. A thematic analysis was conducted. Pregnant women were found to have low awareness about maternal vaccination, with many reporting not having received a recommendation to vaccinate from their doctors. Strong trust in health professionals indicate that strengthened recommendations could improve vaccination uptake. Vaccination decision-making in pregnancy was described in the context of a highly emotional period, generating anxiety and fears around the safety of vaccines. Pregnancy was also discussed as a period during which women develop nurturing and protective identities. However, depending on the information they received as well as influences from experts, families and peers, women either perceived vaccination as a threat to their babies' safety or as a means to protect them. Attitudes towards maternal vaccine trials were less ambiguous, with most pregnant women strongly rejecting the notion of taking part in trials. While strategies to improve pregnant women's awareness and perceptions of maternal vaccination are needed, it is equally important to understand why healthcare professionals may not be recommending vaccination. More coordinated strategies across Europe could help strengthen communication and trust in maternal vaccination. [ABSTRACT FROM AUTHOR]

The provision of gifts and payments for healthy volunteer subjects remains an important topic in global health research ethics. This paper provides empirical insights into theoretical debates by documenting participants' perspectives on an Ebola vaccine trial in West Africa. This trial provided hundreds of Africans with regular payments, food packages and certificates for participation. The researchers conducting the trials considered these socioeconomic provisions to be gifts in accordance with contemporary ethical standards and principles. Trial participants viewed them differently, however, approaching trial participation as a means for training and employment in what was from their perspective a new job market: the post-Ebola expansion of research and health care systems. This paper analyses participation in contemporary research by viewing the context-specific histories of trial participants through the lens of prior interventions, specifically participatory reintegration programmes conducted in Anglophone West Africa to overcome civil war crises. In particular, we argue that participation in the Ebola vaccine trial was inadvertently shaped by the design and outcomes of past reintegration programmes. Our results highlight the need to investigate existing socioeconomic landscapes which surround and indeed permeate clinical research as a prerequisite for understanding the participatory motives of vulnerable participants in West Africa and elsewhere.

Background: The VACCELERATE Pan-European Scientific network aims to strengthen the foundation of vaccine trial research across Europe by following the principles of equity, inclusion, and diversity. The VACCELERATE Volunteer Registry network provides access to vaccine trial sites across the European region and supports a sustainable volunteer platform for identifying potential participants for forthcoming vaccine clinical research., Objective: The aim of this study was to approach members of patient advocacy groups (PAGs) across Europe to assess their willingness to register for the VACCELERATE Volunteer Registry and their perspectives related to participating in vaccine trials., Methods: In an effort to understand how to increase recruitment for the VACCELERATE Volunteer Registry, a standardized survey was developed in English and translated into 8 different languages (Dutch, English, French, German, Greek, Italian, Spanish, and Swedish) by the respective National Coordinator team. The online, anonymous survey was circulated, from March 2022 to May 2022, to PAGs across 10 European countries (Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Spain, and Sweden) to share with their members. The questionnaire constituted of multiple choice and open-ended questions evaluating information regarding participants' perceptions on participating in vaccine trials and their willingness to become involved in the VACCELERATE Volunteer Registry., Results: In total, 520 responses were collected and analyzed. The PAG members reported that the principal criteria influencing their decision to participate in clinical trials overall are (1) the risks involved, (2) the benefits that will be gained from their potential participation, and (3) the quality and quantity of information provided regarding the trial. The survey revealed that, out of the 520 respondents, 133 individuals across all age groups were "positive" toward registering in the VACCELERATE Volunteer Registry, with an additional 47 individuals reporting being "very positive." Respondents from Northern European countries were 1.725 (95% CI 1.206-2.468) times more likely to be willing to participate in the VACCELERATE Volunteer Registry than respondents from Southern European countries., Conclusions: Factors discouraging participants from joining vaccine trial registries or clinical trials primarily include concerns of the safety of novel vaccines and a lack of trust in those involved in vaccine development. These outcomes aid in identifying issues and setbacks in present registries, providing the VACCELERATE network with feedback on how to potentially increase participation and enrollment in trials across Europe. Development of European health communication strategies among diverse public communities, especially via PAGs, is the key for increasing patients' willingness to participate in clinical studies., (©Sophia Themistocleous, Christos D Argyropoulos, Paris Vogazianos, George Shiamakkides, Evgenia Noula, Andria Nearchou, Andreas Yiallouris, Charalampos Filippou, Fiona A Stewart, Markela Koniordou, Ioannis Kopsidas, Helena H Askling, Sirkka Vene, Amandine Gagneux-Brunon, Jana Baranda Prellezo, Elena Álvarez-Barco, Jon Salmanton-García, Janina Leckler, Alan J Macken, Ruth Joanna Davis, Anna Maria Azzini, Charis Armeftis, Margot Hellemans, Romina Di Marzo, Catarina Luis, Ole F Olesen, Olena Valdenmaiier, Stine Finne Jakobsen, Pontus Nauclér, Odile Launay, Patrick Mallon, Jordi Ochando, Pierre van Damme, Evelina Tacconelli, Theoklis Zaoutis, Oliver A Cornely, Zoi Dorothea Pana. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 04.04.2024.)

Evidence on influenza vaccine effectiveness from low and middle countries (LMICs) is limited due to limited institutional capacities; lack of adequate resources; and lack of interest by ministries of health for influenza vaccine introduction. There are concerns that the highest ethical standards will be compromised during trials in LMICs leading to mistrust of clinical trials. These factors pose regulatory and operational challenges to researchers in these countries. We conducted a community-based vaccine trial to assess the efficacy of live attenuated influenza vaccine and inactivated influenza vaccine in rural north India. Key regulatory challenges included obtaining regulatory approvals, reporting of adverse events, and compensating subjects for trial-related injuries; all of which were required to be completed in a timely fashion. Key operational challenges included obtaining audio-visual consent; maintaining a low attrition rate; and administering vaccines during a narrow time period before the influenza season, and under extreme heat. We overcame these challenges through advanced planning, and sustaining community engagement. We adapted the trial procedures to cope with field conditions by conducting mock vaccine camps; and planned for early morning vaccination to mitigate threats to the cold chain. These lessons may help investigators to confront similar challenges in other LMICs.

In clinical trials, it is often of interest to compare and order several candidate regimens based on multiple endpoints. For example, in HIV vaccine development, immune response profiles induced by vaccination are key for selecting vaccine regimens to advance to efficacy evaluation. Motivated by the need to rank and choose a few vaccine regimens based on their immunogenicity in phase I trials, Huang et al. (Biostatistics 18(2):230–243, 2017) proposed a ranking/filtering/selection algorithm that down-selects vaccine regimens to satisfy the superiority and non-redundancy criteria, based on multiple immune response endpoints. In practice, many candidate immune response endpoints can be correlated with each other. An important question that remains to be addressed is how to choose a parsimonious set of the available immune response endpoints to effectively compare regimens. In this paper, we propose novel algorithms for selecting immune response endpoints to be used in regimen down-selection, based on importance weights assigned to individual endpoints and their correlation structure. We show through extensive simulation studies that pre-selection of endpoints can substantially improve performance of the subsequent regimen down-selection process. The application of the proposed method is demonstrated using a real example in HIV vaccine research, although the methods are also applicable in general to clinical research for dimension reduction when comparing regimens based on multiple candidate endpoints. [ABSTRACT FROM AUTHOR]

Background: RTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009-2014 phase III trial (MALARIA-055, NCT00866619), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted.Methods: We implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6-12 weeks) and children (5-17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation.Results: Vaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner.Conclusions: Vegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called "dambos" which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context.Trial Registration: Efficacy of GSK Biologicals' Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009. [ABSTRACT FROM AUTHOR]

The provision of gifts and payments for healthy volunteer subjects remains an important topic in global health research ethics. This paper provides empirical insights into theoretical debates by documenting participants' perspectives on an Ebola vaccine trial in West Africa. This trial provided hundreds of Africans with regular payments, food packages and certificates for participation. The researchers conducting the trials considered these socioeconomic provisions to be gifts in accordance with contemporary ethical standards and principles. Trial participants viewed them differently, however, approaching trial participation as a means for training and employment in what was from their perspective a new job market: the post-Ebola expansion of research and health care systems. This paper analyses participation in contemporary research by viewing the context-specific histories of trial participants through the lens of prior interventions, specifically participatory reintegration programmes conducted in Anglophone West Africa to overcome civil war crises. In particular, we argue that participation in the Ebola vaccine trial was inadvertently shaped by the design and outcomes of past reintegration programmes. Our results highlight the need to investigate existing socioeconomic landscapes which surround and indeed permeate clinical research as a prerequisite for understanding the participatory motives of vulnerable participants in West Africa and elsewhere. [ABSTRACT FROM AUTHOR]

When evaluating principal surrogate biomarkers in vaccine trials, missingness in potential outcomes requires prediction using auxiliary variables and/or augmented study design with a close-out placebo vaccination (CPV) component. The estimated likelihood approach, which separates the estimation of biomarker distribution from the maximization of the estimated likelihood, has often been adopted. Here, we develop a likelihood-based approach that jointly estimates the two parts and describe the methods for selecting auxiliary variables as risk predictors and/or biomarker predictors. Through numerical studies, we observe that in a standard trial design without a CPV component, the two methods achieve similar performance in estimation of the risk model and the marker model. However, for trials augmented with a CPV component, using the likelihood-based method achieves better estimation performance compared to the estimated likelihood method. Moreover, in the presence of a large number of covariates from which to select, the ML method achieves comparable or better performance compared to the EL method in both designs. While the CPV component has not yet been implemented in existing vaccine trials, our results have applications in the planning of future vaccine trials. We illustrate the method using data from a dengue vaccine trial. [ABSTRACT FROM AUTHOR]

A new generation of "bivalent" gp120-based vaccines, effective against subtype B and subtype E viruses, has been developed. Antisera from rabbits and humans immunized with these vaccines are able to neutralize macrophage tropic and T-cell tropic viruses grown in activated peripheral blood mononuclear cells (PBMCs). These vaccines are now available for efficacy trials to determine the role of humoral immunity in providing protection against human immunodeficiency virus type 1 (HIV-1) infection.

African swine fever (ASF) is currently the major concern of the global swine industry, as a consequence of which a reconsideration of the containment and prevention measures taken to date is urgently required. A great interest in developing an effective and safe vaccine against ASF virus (ASFV) infection has, therefore, recently appeared. The objective of the present study is to test an inactivated ASFV preparation under a vaccination strategy that has not previously been tested in order to improve its protective effect. The following have been considered: (i) virus inactivation by using a low binary ethyleneimine (BEI) concentration at a low temperature, (ii) the use of new and strong adjuvants; (iii) the use of very high doses (6 × 109 haemadsorption in 50% of infected cultures (HAD50)), and (iv) simultaneous double inoculation by two different routes of administration: intradermal and intramuscular. Five groups of pigs were, therefore, inoculated with BEI- Pol16/DP/OUT21 in different adjuvant formulations, twice with a 4-week interval. Six weeks later, all groups were intramuscularly challenged with 10 HAD50 of the virulent Pol16/DP/OUT21 ASFV isolate. All the animals had clinical signs and pathological findings consistent with ASF. This lack of effectiveness supports the claim that an inactivated virus strategy may not be a viable vaccine option with which to fight ASF.

In early 2020, adult volunteers were invited to participate in a first-in-human trial of the COVID-19 vaccine, ChAdOx1 nCoV-19, in the United Kingdom (UK) at the height of the global pandemic when there was uncertainty regarding vaccine efficacy and side-effects. We conducted a retrospective survey of these uniquely situated individuals to gain insight into their views about the risks, motivations, and expectations of the trial and potential vaccine deployment. Our data from 349 respondents show that these volunteers were educated to a high-level with a clear understanding of the seriousness of the COVID-19 pandemic, as well as an appreciation of the role of science and research in developing a vaccine to address this global problem. Individuals were primarily motivated with altruistic intent and expressed a desire to contribute to the scientific effort. Respondents appreciated that their participation was associated with risk but appeared comfortable that this risk was low. Through our analysis, we highlight these individuals as a group with strong levels of trust in science and a sense of societal responsibility, and therefore are a potential valuable resource to improve confidence in novel vaccines. Vaccine trial participants could offer a credible collective voice to support positive messaging around vaccination.

From 1992 to 2007, the ANRS (France Recherche Nord & Sud Sida-HIV Hépatites) set up a network of healthy volunteers at low risk of HIV infection and participating in preventive HIV vaccine phase I and II trials. The objectives of the ANRS COHVAC volunteer cohort include the social consequences of trial participation and their sexual behavior over time. For 488 volunteers who received a vaccine candidate, 462 selection files were collected, and from 2008 to 2016, 355 volunteers participated in the prospective cohort, including self-administered and face-to-face questionnaires administered annually. The volunteer population is relatively old, with social characteristics and engagement in society rather high. Most volunteers and people around them well accepted the trials, and participation in vaccine trials was not followed by increased risk-taking regarding HIV infection years later. [ABSTRACT FROM AUTHOR]

We present an approximate posterior inference methodology for a Bayesian hierarchical mixed-effect Poisson regression model. The model serves us to address the multiple testing problem in the presence of many group or clus-ter effects. This is carried out through a specialized Bayesian false discovery rate procedure. The likelihood is simplified by an approximation based on Laplace's approximation for integrals and a trace approximation for the de-terminants. The posterior marginals are estimated using this approximated likelihood. In particular, we obtain credible regions for the parameters, as well as probability estimates for the difference between risks (Poisson inten-sities) associated with different groups or clusters, or different levels of the fixed effects. The methodology is illustrated through an application to a vaccine trial. [ABSTRACT FROM AUTHOR]

Background/aims: Network structure and individuals' level of exposure to a pathogen can impact results from efficacy evaluation studies of interventions against infectious diseases. Heterogeneity in infection risk can cause randomized groups to increasingly differ as a trial progresses and as more high-risk individuals become infected (described in prior work as the ''frailty'' phenomenon). Here, we show the impact this phenomenon can have on an individually randomized trial of a leaky vaccine in which all participants are exchangeable a priori. Methods: We model a vaccine trial by generating a network of individuals grouped into communities, which are connected to a larger main population. We then simulate an epidemic, deterministically and with time-varying transmission rates in the main population and stochastically in the communities. The disease natural history follows a susceptible-exposed-infectious-recovered model. Simulation results are used to estimate vaccine efficacy (c VE) with a Cox proportional hazards model. Results: We find downward bias in c VE associated with low connectivity between communities in the study population and high force of infection, even when all participants in the trial are exchangeable at the time of randomization. This phenomenon arises because the stochastic dynamics in such a setting randomly lead to community-level variation in the force of infection. Stratifying a Cox model by community alleviates this bias with no loss of power. Conclusion: Understanding and accounting for the impact of heterogeneous hazard rates can allow for more accurate estimates of c VE in epidemic settings. [ABSTRACT FROM AUTHOR]