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

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

Host-parasite interactio

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

Corrigendum: Controlled Human Infections As a Tool to Reduce Uncertainty in Clinical Vaccine Development

Host-parasite interactio

The frontline of controlled human malaria infections: A report from the controlled human infection models Workshop in Leiden University Medical Centre 5 May 2016

Host-parasite interactio

Strategic and scientific contributions of human challenge trials for vaccine development: facts versus fantasy

The unprecedented speed of delivery of SARS-CoV-2 pandemic vaccines has redefined the limits for all vaccine development. Beyond the aspirational 100-day timeline for tomorrow's hypothetical pandemic vaccines, there is a sense of optimism that development of other high priority vaccines can be accelerated. Early in the COVID-19 pandemic, an intense and polarised academic and public discourse arose concerning the role of human challenge trials for vaccine development. A case was made for human challenge trials as a powerful tool to establish early proofof-concept of vaccine efficacy in humans, inform vaccine down selection, and address crucial knowledge gaps regarding transmission, pathogenesis, and immune protection. We review the track record of human challenge trials contributing to the development of vaccines for 19 different pathogens and discuss relevant limitations, barriers, and pitfalls. This Review also highlights opportunities for efforts to broaden the scope and boost the effects of human challenge trials, to accelerate all vaccine development.Host-parasite interactio

Immunological considerations for schistosoma vaccine development: transitioning to endemic settings

Despite mass drug administration programmes with praziquantel, the prevalence of schistosomiasis remains high. A vaccine is urgently needed to control transmission of this debilitating disease. As some promising schistosomiasis vaccine candidates are moving through pre-clinical and clinical testing, we review the immunological challenges that these vaccine candidates may encounter in transitioning through the clinical trial phases in endemic settings. Prior exposure of the target population to schistosomes and other infections may impact vaccine response and efficacy and therefore requires considerable attention. Schistosomes are known for their potential to induce T-reg/IL-10 mediated immune suppression in populations which are chronically infected. Moreover, endemicity of schistosomiasis is focal whereby target and trial populations may exhibit several degrees of prior exposure as well as in utero exposure which may increase heterogeneity of vaccine responses. The age dependent distribution of exposure and development of acquired immunity, and general differences in the baseline immunological profile, adds to the complexity of selecting suitable trial populations. Similarly, prior or concurrent infections with other parasitic helminths, viral and bacterial infections, may alter immunological responses. Consequently, treatment of co-infections may benefit the immunogenicity of vaccines and may be considered despite logistical challenges. On the other hand, viral infections leave a life-long immunological imprint on the human host. Screening for serostatus may be needed to facilitate interpretation of vaccine responses. Co-delivery of schistosome vaccines with PZQ is attractive from a perspective of implementation but may complicate the immunogenicity of schistosomiasis vaccines. Several studies have reported PZQ treatment to induce both transient and long-term immuno-modulatory effects as a result of tegument destruction, worm killing and subsequent exposure of worm antigens to the host immune system. These in turn may augment or antagonize vaccine immunogenicity. Understanding the complex immunological interactions between vaccine, co-infections or prior exposure is essential in early stages of clinical development to facilitate phase 3 clinical trial design and implementation policies. Besides well-designed studies in different target populations using schistosome candidate vaccines or other vaccines as models, controlled human infections could also help identify markers of immune protection in populations with different disease and immunological backgrounds.Host-parasite interactio

Long Term Protection after Immunization with P. berghei Sporozoites Correlates with Sustained IFNγ Responses of Hepatic CD8+ Memory T Cells

Protection against P. berghei malaria can successfully be induced in mice by immunization with both radiation attenuated sporozoites (RAS) arresting early during liver stage development, or sporozoites combined with chloroquine chemoprophylaxis (CPS), resulting in complete intra-hepatic parasite development before killing of blood-stages by chloroquine takes place. We assessed the longevity of protective cellular immune responses by RAS and CPS P. berghei immunization of C57BL/6j mice. Strong effector and memory (TEM) CD8+ T cell responses were induced predominantly in the liver of both RAS and CPS immunized mice while CD4+ T cells with memory phenotype remained at base line levels. Compared to unprotected naïve mice, we found high sporozoite-specific IFNγ ex vivo responses that associated with induced levels of in vivo CD8+ TEM cells in the liver but not spleen. Long term evaluation over a period of 9 months showed a decline of malaria-specific IFNγ responses in RAS and CPS mice that significantly correlated with loss of protection (r2 = 0.60, p<0.0001). The reducing IFNγ response by hepatic memory CD8+ T cells could be boosted by re-exposure to wild-type sporozoites. Our data show that sustainable protection against malaria associates with distinct intra-hepatic immune responses characterized by strong IFNγ producing CD8+ memory T cells