Experience and Challenges from Clinical Trials with Malaria Vaccines in Africa.

Malaria vaccines are considered amongst the most important modalities for potential elimination of malaria disease and transmission. Research and development in this field has been an area of intense effort by many groups over the last few decades. Despite this, there is currently no licensed malaria vaccine. Researchers, clinical trialists and vaccine developers have been working on many approached to make malaria vaccine available.African research institutions have developed and demonstrated a great capacity to undertake clinical trials in accordance to the International Conference on Harmonization-Good Clinical Practice (ICH-GCP) standards in the last decade; particularly in the field of malaria vaccines and anti-malarial drugs. This capacity is a result of networking among African scientists in collaboration with other partners; this has traversed both clinical trials and malaria control programmes as part of the Global Malaria Action Plan (GMAP). GMAP outlined and support global strategies toward the elimination and eradication of malaria in many areas, translating in reduction in public health burden, especially for African children. In the sub-Saharan region the capacity to undertake more clinical trials remains small in comparison to the actual need.However, sustainability of the already developed capacity is essential and crucial for the evaluation of different interventions and diagnostic tools/strategies for other diseases like TB, HIV, neglected tropical diseases and non-communicable diseases. There is urgent need for innovative mechanisms for the sustainability and expansion of the capacity in clinical trials in sub-Saharan Africa as the catalyst for health improvement and maintained

Infectieziekten zonder grenzen

Diesoratie uitgesproken door Prof.dr. Meta Roestenberg Professor Humane modellen voor vaccinontwikkelingtijdens de 447ste dies natalis op dinsdag 8 februari 2022 in de PieterskerkLUMC / Geneeskund

Money-oriented risk-takers or deliberate decision-makers: a cross-sectional survey study of participants in controlled human infection trials

Objective To quantitatively investigate the motivations, decision-making and experience of participants in controlled human infection (CHI) studies.Design Cross-sectional descriptive survey study.Setting Previous participants of CHI studies at the Leiden Controlled Human Infection Center, control group of students from Leiden University.Participants 61 previous participants and 156 controls.Measurements Ranking of motivational and decisional factors, risk propensity score and multiple-choice questions on experience of trial participation and ethical aspects of CHI studies.Results Motivating factors for participants were contributing to science (81%), contributing to research that may benefit developing countries (72%) and the financial compensation (63%). For 51% of participants, a reason other than financial compensation was the most important motivational factor. Participants considered trust in the study team (70%), time investment (63%), severity of symptoms (54%), chance of developing symptoms (54%) and whether it is an easy way to make money (54%) in their decision to participate. Most CHI participants (84%) were proud of their participation, would advise others to participate (89%) and would participate in a similar trial again (85%). CHI participants had a higher risk propensity score than students (estimated difference 0.9, pConclusion Although financial compensation is important, the motivations for participants in a CHI study are diverse and participants make a balanced appraisal of risks and burden before participating.Host-parasite interactio

Down selecting adjuvanted vaccine formulations: a comparative method for harmonized evaluation.

The need for rapid and accurate comparison of panels of adjuvanted vaccine formulations and subsequent rational down selection, presents several challenges for modern vaccine development. Here we describe a method which may enable vaccine and adjuvant developers to compare antigen/adjuvant combinations in a harmonized fashion. Three reference antigens: Plasmodium falciparum apical membrane antigen 1 (AMA1), hepatitis B virus surface antigen (HBsAg), and Mycobacterium tuberculosis antigen 85A (Ag85A), were selected as model antigens and were each formulated with three adjuvants: aluminium oxyhydroxide, squalene-in-water emulsion, and a liposome formulation mixed with the purified saponin fraction QS21. The nine antigen/adjuvant formulations were assessed for stability and immunogenicity in mice in order to provide benchmarks against which other formulations could be compared, in order to assist subsequent down selection of adjuvanted vaccines. Furthermore, mouse cellular immune responses were analyzed by measuring IFN-γ and IL-5 production in splenocytes by ELISPOT, and humoral responses were determined by antigen-specific ELISA, where levels of total IgG, IgG1, IgG2b and IgG2c in serum samples were determined. The reference antigens and adjuvants described in this study, which span a spectrum of immune responses, are of potential use as tools to act as points of reference in vaccine development studies. The harmonized methodology described herein may be used as a tool for adjuvant/antigen comparison studies

Controlled human infection models to evaluate schistosomiasis and hookworm vaccines: where are we now?

Host-parasite interactio

CD8+ T cells from a novel T cell receptor transgenic mouse induce liver-stage immunity that can be boosted by blood-stage infection in rodent malaria

To follow the fate of CD8+ T cells responsive to Plasmodium berghei ANKA (PbA) infection, we generated an MHC I-restricted TCR transgenic mouse line against this pathogen. T cells from this line, termed PbT-I T cells, were able to respond to blood-stage infection by PbA and two other rodent malaria species, P. yoelii XNL and P. chabaudi AS. These PbT-I T cells were also able to respond to sporozoites and to protect mice from liver-stage infection. Examination of the requirements for priming after intravenous administration of irradiated sporozoites, an effective vaccination approach, showed that the spleen rather than the liver was the main site of priming and that responses depended on CD8α+ dendritic cells. Importantly, sequential exposure to irradiated sporozoites followed two days later by blood-stage infection led to augmented PbT-I T cell expansion. These findings indicate that PbT-I T cells are a highly versatile tool for studying multiple stages and species of rodent malaria and suggest that cross-stage reactive CD8+ T cells may be utilized in liver-stage vaccine design to enable boosting by blood-stage infections

What motivates SARS-CoV-2 vaccine trial participants?: A pre- and post-participation survey study

BackgroundScientific advancement, including the testing and licensing of new drugs, relies heavily on clinical trials with healthy individuals. The motivations of clinical trial participants have been discussed intensively, as some worry that financial compensation may distract from the intrinsic risk of clinical research. Herein, we investigated the motivations and decisional factors influencing SARS-CoV-2 clinical trial participants. Moreover, since most surveys are administered after clinical trial participation, we were interested in whether the results were tainted by recall bias.MethodsThis was a cross-sectional observational study. Participants were administered a survey on two occasions, once before and once after participation in a clinical trial. The primary outcomes were the motivations and decisional factors of SARS-CoV-2 vaccine trial participants and the difference between the surveys collected before and after clinical trial participation.ResultsThe survey response rate was 149/200 (75%). SARS-CoV-2 vaccine trial participants were mostly motivated by the desire to contribute to science and help others. Answers collected before and after the trial were not statistically different, indicating the absence of recall bias.ConclusionThe decision-making process of clinical trial participants is complex and multi-faceted. Previous studies have shown that clinical trial participants have mixed motivations but never to the extent reported in the current survey. Here, we present a theoretical framework that attempts to explain how different motivational factors may contribute to decision forming.Host-parasite interactio

Immune mechanisms in malaria: new insights in vaccine development.

Early data emerging from the first phase 3 trial of a malaria vaccine are raising hopes that a licensed vaccine will soon be available for use in endemic countries, but given the relatively low efficacy of the vaccine, this needs to be seen as a major step forward on the road to a malaria vaccine rather than as arrival at the final destination. The focus for vaccine developers now moves to the next generation of malaria vaccines, but it is not yet clear what characteristics these new vaccines should have or how they can be evaluated. Here we briefly review the epidemiological and immunological requirements for malaria vaccines and the recent history of malaria vaccine development and then put forward a manifesto for future research in this area. We argue that rational design of more effective malaria vaccines will be accelerated by a better understanding of the immune effector mechanisms involved in parasite regulation, control and elimination

Imaging as a (pre)clinical tool in parasitology

Imaging of parasites is central to diagnosis of many parasitic diseases and has thus far played an important role in the development of antiparasitic strategies. The development of novel imaging technologies has revolutionized medicine in fields other than parasitology and has also opened up new avenues for the visu-alization of parasites. Here we review the role imaging technology has played so far in parasitology and how it may spur further advancement. We point out possibilities to improve current microscopy-based diagnostic methods and how to extend them with radiological imaging modalities. We also highlight in vivo tracking of parasites as a readout for efficacy of new antiparasitic strate-gies and as a source of fundamental insights for rational design.Radiolog

Assessment of risks associated with severe acute respiratory syndrome Coronavirus 2 experimental human infection studies

Controlled human infection (CHI) models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been proposed as a tool to accelerate the development of vaccines and drugs. Such models carry inherent risks. Participants may develop severe disease or complications after deliberate infection. Prolonged isolation may negatively impact their well-being. Through secondary infection of study personnel or participant household contacts, the experimental virus strain may cause a community outbreak. We identified risks associated with such a SARS-CoV-2 CHI model and assessed their likelihood and impact and propose strategies that mitigate these risks. In this report, we show that risks can be minimized with proper risk mitigation strategies; the residual risk, however, should be weighed carefully against the scientific and social values of such a CHI model.Clinical epidemiolog