Recombinant Full-length Plasmodium falciparum Circumsporozoite Protein-Based Vaccine Adjuvanted With Glucopyranosyl Lipid A-Liposome Quillaja saponaria 21: Results of Phase 1 Testing With Malaria Challenge.

BACKGROUND: Malaria is preventable yet causes >600 000 deaths annually. RTS,S, the first marketed malaria vaccine, has modest efficacy, but improvements are needed for eradication. METHODS: We conducted an open-label, dose escalation phase 1 study of a full-length recombinant circumsporozoite protein vaccine (rCSP) administered with adjuvant glucopyranosyl lipid A-liposome Quillaja saponaria 21 formulation (GLA-LSQ) on days 1, 29, and 85 or 1 and 490 to healthy, malaria-naive adults. The primary end points were safety and reactogenicity. The secondary end points were antibody responses and Plasmodium falciparum parasitemia after homologous controlled human malaria infection. RESULTS: Participants were enrolled into 4 groups receiving rCSP/GLA-LSQ: 10 µg × 3 (n = 20), 30 µg × 3 (n = 10), 60 µg × 3 (n = 10), or 60 µg × 2 (n = 9); 10 participants received 30 µg rCSP alone × 3, and there were 6 infectivity controls. Participants experienced no serious adverse events. Rates of solicited and unsolicited adverse events were similar among groups. All 26 participants who underwent controlled human malaria infection 28 days after final vaccinations developed malaria. Increasing vaccine doses induced higher immunoglobulin G titers but did not achieve previously established RTS,S benchmarks. CONCLUSIONS: rCSP/GLA-LSQ had favorable safety results. However, tested regimens did not induce protective immunity. Further investigation could assess whether adjuvant or schedule adjustments improve efficacy. CLINICAL TRIALS REGISTRATION: NCT03589794.

Optimizing the Immunogenicity of HIV Vaccines by Adjuvants - NIAID Workshop Report.

This report summarizes the highlights of a workshop convened by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), on April 4-5, 2022, to provide a discussion forum for sharing insights on the current status, key challenges, and next steps to advance the current landscape of promising adjuvants in preclinical and clinical human immunodeficiency virus (HIV) vaccine studies. A key goal was to solicit and share recommendations on scientific, regulatory, and operational guidelines for bridging the gaps in rational selection, access, and formulation of clinically relevant adjuvants for HIV vaccine candidates. The NIAID Vaccine Adjuvant Program working group remains committed to accentuate promising adjuvants and nurturing collaborations between adjuvant and HIV vaccine developers.

Meeting Summary: Global Vaccine and Immunization Research Forum, 2021.

The 2021 Global Vaccine and Immunization Research Forum highlighted the considerable advances and recent progress in research and development for vaccines and immunization, critically reviewed lessons learned from COVID-19 vaccine programs, and looked ahead to opportunities for this decade. For COVID-19, decades of investments in basic and translational research, new technology platforms, and vaccines targeting prototype pathogens enabled a rapid, global response. Unprecedented global coordination and partnership have played an essential role in creating and delivering COVID-19 vaccines. More improvement is needed in product attributes such as deliverability, and in equitable access to vaccines. Developments in other priority areas included: the halting of two human immunodeficiency virus vaccine trials due to lack of efficacy in preventing infection; promising efficacy results in Phase 2 trials of two tuberculosis vaccines; pilot implementation of the most advanced malaria vaccine candidate in three countries; trials of human papillomavirus vaccines given in single-dose regimens; and emergency use listing of a novel, oral poliomyelitis type 2 vaccine. More systematic, proactive approaches are being developed for fostering vaccine uptake and demand, aligning on priorities for investment by the public and private sectors, and accelerating policy making. Participants emphasized that addressing endemic disease is intertwined with emergency preparedness and pandemic response, so that advances in one area create opportunities in the other. In this decade, advances made in response to the COVID-19 pandemic should accelerate availability of vaccines for other diseases, contribute to preparedness for future pandemics, and help to achieve impact and equity under Immunization Agenda 2030.

Low dose recombinant full-length circumsporozoite protein-based Plasmodium falciparum vaccine is well-tolerated and highly immunogenic in phase 1 first-in-human clinical testing.

Plasmodium falciparum circumsporozoite protein (CSP) is a major sporozoite surface protein and a key target of pre-erythrocytic malaria subunit vaccines. A full-length recombinant CSP (rCSP) based strategy could be advantageous, as this antigen includes a region critical to sporozoite cell attachment and hepatocyte invasion. The adjuvant Glucopyranosyl Lipid A-liposome Quillaja saponaria 21 (GLA-LSQ) functions as a TLR4 agonist, promotes antigen-specific TH1 responses and stimulates cytotoxic T cell production. To date, one study has reported the clinical acceptability of GLA-LSQ. We present interim results of a phase 1 first-in-human dose-escalation clinical trial of full-length rCSP vaccine given with or without GLA-LSQ adjuvant. Participants experienced only mild to moderate related solicited adverse events. The lowest adjuvanted vaccine dose achieved >90-fold rise in geometric mean anti-CSP IgG antibody titer. These favorable safety and immunogenicity results confirm the immunostimulatory capacity of this relatively new adjuvant and support next steps in clinical product development. Trial registration: ClinicalTrials.gov Identifier NCT03589794 (registered 18 July 2018).

Understanding vaccine-elicited protective immunity against pre-erythrocytic stage malaria in endemic regions.

Recent malaria vaccine trials in endemic areas have yielded disparate results compared to studies conducted in non-endemic areas. A workshop was organized to discuss the differential pre-erythrocytic stage malaria vaccine (Pre-E-Vac) efficacies and underlying protective immunity under various conditions. It was concluded that many factors, including vaccine technology platforms, host genetics or physiologic conditions, and parasite and mosquito vector variations, may all contribute to Pre-E-Vac efficacy. Cross-disciplinary approaches are needed to decipher the multi-dimensional variables that contribute to the observed vaccine hypo-responsiveness. The malaria vaccine community has an opportunity to leverage recent advances in immunology, systems vaccinology, and high dimensionality data science methodologies to generate new clinical datasets with unprecedented levels of functional resolution as well as capitalize on existing datasets for comprehensive and aggregate analyses. These approaches would help to unlock our understanding of Pre-E-Vac immunology and to translate new candidates from the laboratory to the field more predictably.

Understanding the Liver-Stage Biology of Malaria Parasites: Insights to Enable and Accelerate the Development of a Highly Efficacious Vaccine.

In August 2017, the National Institute of Allergy and Infectious Diseases convened a meeting, entitled "Understanding the Liver-Stage Biology of Malaria Parasites to Enable and Accelerate the Development of a Highly Efficacious Vaccine," to discuss the needs and strategies to develop a highly efficacious, whole organism-based vaccine targeting the liver stage of malaria parasites. It was concluded that attenuated sporozoite platforms have proven to be promising approaches, and that late-arresting sporozoites could potentially offer greater vaccine performance than early-arresting sporozoites against malaria. New knowledge and emerging technologies have made the development of late-arresting sporozoites feasible. Highly integrated approaches involving liver-stage research, "omics" studies, and cutting-edge genetic editing technologies, combined with in vitro culture systems or unique animal models, are needed to accelerate the discovery of candidates for a late-arresting, genetically attenuated parasite vaccine.

Controlled human infections: A report from the controlled human infection models workshop, Leiden University Medical Centre 4-6 May 2016.

The principle of deliberately infecting humans with infectious agents in a controlled setting, so-called controlled human infections (CHI), is not novel. Many CHI models have a long history and were established decades ago such as the intentional exposure to yellow fever and dengue performed in the 1900's (Reed, 1902) [2]. In these times bioethics and scientific reasoning were in their infancy. Nowadays, clinical trials are highly regulated and CHI are executed worldwide. Controlled human malaria infections and influenza infections are the two most frequently practiced. Others are experiencing a revival or are being carefully developed. Because CHI models test the efficacy of promising vaccine or drug candidates early in clinical development, they offer the potential to decrease the number of failing phase 2 and 3 trials, reducing risks for patients and saving costs and efforts. In addition, CHI models provide unprecedented opportunities to dissect the physiological, immunological and metabolic changes that occur upon infection. However, it is clear that controlled infections require careful deliberation of safety, ethics, quarantine, scientific output and the production of infectious material. An independent international workshop was hosted by the Leiden University Medical Centre in The Netherlands, bringing together clinical investigators, basic scientists, regulators, funders and policy makers from 22 different countries to discuss the opportunities and challenges in CHI. The aim of the workshop was to discuss CHI as a tool to advance science, drug and vaccine development, share the challenges of establishing a CHI model with specific focus on neglected tropical diseases and the possibilities to transfer models to endemic sites. Noticeably, among the 128 participants were clinical investigators from ten different countries in Sub-Saharan Africa. An important dimension of the meeting was to give the floor to young established clinicians and scientists to voice their perspective on the future of CHI models.

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

Controlled Human Malaria Infection (CHMI) is the most practiced controlled human infection model nowadays and there is an exponential increase in implementation of the model worldwide. During the Controlled Human Infection Models Workshop in Leiden, one day was dedicated to the discussion of the advances made and gaps in Controlled Human Malaria Infection (CHMI) trials. Factors contributing to this impressive expansion in the number of CHMI trials have been related to the ability to perform CHMI using injectable cryopreserved sporozoites (a product from Sanaria Inc. - PfSPZ Challenge), the development of a transmission blocking CHMI model and the need to test more vaccine candidates particularly in the field of whole-sporozoite vaccine development. However, with an increasing number of CHMI trials being undertaken, in an ever-growing number of trial sites, heterogeneity in trial design may compromise universal interpretation of results and require an ongoing dialogue on the need and feasibility of standardization. At the workshop, CHMI investigators convened to share their experiences in CHMI trials and discuss the possibilities for future trials.

Waning Immunity and Microbial Vaccines-Workshop of the National Institute of Allergy and Infectious Diseases.

Since the middle of the 20th century, vaccines have made a significant public health impact by controlling infectious diseases globally. Although long-term protection has been achieved with some vaccines, immunity wanes over time with others, resulting in outbreaks or epidemics of infectious diseases. Long-term protection against infectious agents that have a complex life cycle and antigenic variation remains a key challenge. Novel strategies to characterize the short- and long-term immune responses to vaccines and to induce immune responses that mimic natural infection have recently emerged. New technologies and approaches in vaccinology, such as adjuvants, delivery systems, and antigen formulations, have the potential to elicit more durable protection and fewer adverse reactions; together with in vitro systems, these technologies have the capacity to model and accelerate vaccine development. The National Institute of Allergy and Infectious Diseases (NIAID) held a workshop on 19 September 2016 that focused on waning immunity to selected vaccines (for Bordetella pertussis, Salmonella enterica serovar Typhi, Neisseria meningitidis, influenza, mumps, and malaria), with an emphasis on identifying knowledge gaps, future research needs, and how this information can inform development of more effective vaccines for infectious diseases.

Workshop report: Schistosomiasis vaccine clinical development and product characteristics.

A schistosomiasis vaccine meeting was organized to evaluate the utility of a vaccine in public health programs, to discuss clinical development paths, and to define basic product characteristics for desirable vaccines to be used in the context of schistosomiasis control and elimination programs. It was concluded that clinical evaluation of a schistosomiasis vaccine is feasible with appropriate trial design and tools. Some basic Preferred Product Characteristics (PPC) for a human schistosomiasis vaccine and for a veterinary vaccine for bovine use were also proposed.

Exploring immunological mechanisms of the whole sporozoite vaccination against P. falciparum malaria.

Great progress has been made in the development of whole sporozoite vaccines including the manufacturing of cryopreserved Plasmodium falciparum sporozoites (PfSPZ) suitable for clinical application. Such whole sporozoites are being used for clinical studies of controlled human malaria infection (CHMI) as well as for evaluation of candidate vaccine approaches (both attenuated sporozoites and infectious sporozoites administered with chemoprophylaxis) and as reagents for immunology and cell biology assays. CHMI studies with whole sporozoites provide a great opportunity to better understand the intrinsic mechanisms of resistance to P. falciparum (e.g. due to sickle cell trait and other hemoglobinopathies) as well as host responses to an initial P. falciparum infection. High-level protective efficacy has been demonstrated in a small number of volunteers after intravenous (IV) inoculation of radiation-attenuated PfSPZ or in those who were exposed to live PfSPZ while on malaria chemoprophylaxis. These advances and data warrant further investigations of the immunological mechanism(s) whereby whole sporozoite inoculation elicits protective immunity in order to facilitate whole sporozoite vaccine development. The National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on Sept. 2-3, 2014 involving participation of international experts in the field of malaria vaccine development, and in basic and clinical immunology research. The workshop discussed the current understanding of host immune responses to whole malaria sporozoite inoculation, identified gaps in knowledge, resources to facilitate progress, and applicable new technologies and approaches to accelerate immunologic and vaccinologic studies and biomarker identification. This report summarizes the discussions and major conclusions from the workshop participants.

Schistosomiasis elimination strategies and potential role of a vaccine in achieving global health goals.

In March 2013, the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation co-sponsored a meeting entitled "Schistosomiasis Elimination Strategy and Potential Role of a Vaccine in Achieving Global Health Goals" to discuss the potential role of schistosomiasis vaccines and other tools in the context of schistosomiasis control and elimination strategies. It was concluded that although schistosomiasis elimination in some focal areas may be achievable through current mass drug administration programs, global control and elimination will face several significant scientific and operational challenges, and will require an integrated approach with other, additional interventions. These challenges include vector (snail) control; environmental modification; water, sanitation, and hygiene; and other future innovative tools such as vaccines. Defining a clear product development plan that reflects a vaccine strategy as complementary to the existing control programs to combat different forms of schistosomiasis will be important to develop a vaccine effectively.

NIAID meeting report: improving malaria vaccine strategies through the application of immunological principles.

A highly efficacious vaccine to prevent malaria infection or clinical disease is still far from reality despite several decades of intensive effort and a growing global commitment in malaria vaccine development. Further understanding of the mechanisms required for induction of effective host immune responses and maintenance of long-term protective immunity is needed to facilitate rational approaches for vaccine design and evaluation. The National Institute of Allergy and Infectious Diseases (NIAID) conducted a workshop on June 18-19, 2012 with experts in the fields of malaria vaccine development, malaria immunology, and basic immunology to address issues associated with improving our current understanding of malaria vaccine immunity. This report summarizes the discussion and major recommendations generated by the workshop participants regarding the application of recent advances in basic immunology and state-of-the-art immunological tools to improve progress and help address current challenges and knowledge gaps in malaria vaccine development.

A heat shock protein based polyvalent vaccine targeting HSV-2: CD4(+) and CD8(+) cellular immunity and protective efficacy.

Efforts to develop a subunit vaccine against genital herpes have been hampered by lack of knowledge of the protective antigens of HSV-2, the causative agent of the disease. Vaccines based either on selected antigens or attenuated live virus approaches have not demonstrated meaningful clinical activity. We present here results of a therapeutic vaccine candidate, HerpV (formerly called AG-707), consisting of 32 HSV-2 peptides derived from 22 HSV-2 proteins, complexed non-covalently to the HSP70 chaperone and formulated with QS-21 saponin adjuvant. HerpV is observed to be immunogenic, generating CD4(+) and CD8(+) T cell responses in three mouse strains including HLA-A2 transgenic mice. Optimal T cell stimulation was dependent on the synergistic adjuvant properties of QS-21 with hsp70. The vaccine provided significant protection from viral challenge in a mouse prophylaxis model and showed signals of activity in a guinea pig therapeutic model of existing infection. Peripheral blood mononuclear cells from human HSV-2(+) subjects also showed reactivity in vitro to a subset of individual peptides and to the pool of all 32 peptides. Recombinant human Hsc70 complexed with the 32 peptides also stimulated the expansion of CD8(+) T cells from HSV-2(+) subjects in vitro. These studies demonstrate that HerpV is a promising immunotherapy candidate for genital herpes, and provide a foundation for evaluating HerpV in human HSV-2(+) subjects with the intent of eliciting CD4(+) and CD8(+) T cell responses to a broad array of viral antigens.

NIAID workshop on immunity to malaria: addressing immunological challenges.

The US National Institute of Allergy and Infectious Diseases convened a workshop of malaria investigators and immunologists to foster collaborations and attract more immunologists into malaria research. Discussions highlighted research gaps and underscored the incomplete understanding of basic immune mechanisms that contribute to the pathogenesis of or protection against malaria.

Current vaccine adjuvants: an overview of a diverse class.

Numerous compounds are under evaluation as immunological adjuvants for improvement of vaccine performance. This review will briefly summarize some of the many diverse substances that are currently being utilized as vaccine adjuvants in preclinical and clinical studies.

The cytosolic endopeptidase, thimet oligopeptidase, destroys antigenic peptides and limits the extent of MHC class I antigen presentation.

Most antigenic peptides presented on MHC class I molecules are generated by proteasomes during protein breakdown. It is unknown whether these peptides are protected from destruction by cytosolic peptidases. In cytosolic extracts, most antigenic peptides are degraded by the metalloendopeptidase, thimet oligopeptidase (TOP). We therefore examined whether TOP destroys antigenic peptides in vivo. When TOP was overexpressed in cells, class I presentation of antigenic peptides was reduced. In contrast, TOP overexpression didn't reduce presentation of peptides generated in the endoplasmic reticulum or endosomes. Conversely, preventing TOP expression with siRNA enhanced presentation of antigenic peptides. TOP therefore plays an important role in vivo in degrading peptides released by proteasomes and is a significant factor limiting the extent of antigen presentation.