A randomized clinical trial of the impact of melatonin on influenza vaccine: Outcomes from the melatonin and vaccine response immunity and chronobiology study (MAVRICS).

Vaccine immunogenicity is affected by a variety of factors. Melatonin has been reported to affect immune responses to vaccines and infection. This was a randomized open-label trial - in which adults scheduled to receive the influenza vaccine were randomized to 5 mg melatonin or control to evaluate the effect of post-vaccination melatonin on humoral (hemagglutination-inhibition assays, HAI) and cellular (FluoroSpot) vaccine-specific cytokine responses 14-21 days post-vaccination.

AMA1 and CSP antigen diversity in parasite isolates from southern Ghana.

Introduction: Diversity in malarial antigens is an immune evasion mechanism that gives malaria parasites an edge over the host. Immune responses against one variant of a polymorphic antigen are usually not fully effective against other variants due to altered epitopes. This study aimed to evaluate diversity in the Plasmodium falciparum antigens apical membrane antigen 1 (PfAMA1) and circumsporozoite protein (PfCSP) from circulating parasites in a malaria-endemic community in southern Ghana and to determine the effects of polymorphisms on antibody response specificity.

Induction of antigen specific intrahepatic CD8+ T cell responses by a secreted heat shock protein based gp96-Ig-PfCA malaria vaccine.

Introduction: A highly efficacious and durable vaccine against malaria is an essential tool for global malaria eradication. One of the promising strategies to develop such a vaccine is to induce robust CD8+ T cell mediated immunity against malaria liver-stage parasites.

Methods: Here we describe a novel malaria vaccine platform based on a secreted form of the heat shock protein, gp96-immunoglobulin, (gp96-Ig) to induce malaria antigen specific, memory CD8+ T cells.

Immunodominant T cell peptides from four candidate malarial antigens as biomarkers of protective immunity against malaria.

A malaria vaccine with high efficacy and capable of inducing sterile immunity against malaria within genetically diverse populations is urgently needed to complement ongoing disease control and elimination efforts. Parasite-specific IFN-γ and granzyme B-secreting CD8 + T cells have been identified as key mediators of protection and the rapid identification of malaria antigen targets that elicit these responses will fast-track the development of simpler, cost-effective interventions. This study extends our previous work which used peripheral blood mononuclear cells (PBMCs) from adults with life-long exposure to malaria parasites to identify immunodominant antigen-specific peptide pools composed of overlapping 15mer sequences spanning full length proteins of four malarial antigens.

In vitro production of infectious Plasmodium falciparum sporozoites.

An effective vaccine is needed for the prevention and elimination of malaria. The only immunogens that have been shown to have a protective efficacy of more than 90% against human malaria are Plasmodium falciparum (Pf) sporozoites (PfSPZ) manufactured in mosquitoes (mPfSPZ). The ability to produce PfSPZ in vitro (iPfSPZ) without mosquitoes would substantially enhance the production of PfSPZ vaccines and mosquito-stage malaria research, but this ability is lacking.

Cellular interferon-gamma and interleukin-2 responses to SARS-CoV-2 structural proteins are broader and higher in those vaccinated after SARS-CoV-2 infection compared to vaccinees without prior SARS-CoV-2 infection.

Class I- and Class II-restricted epitopes have been identified across the SARS-CoV-2 structural proteome. Vaccine-induced and post-infection SARS-CoV-2 T-cell responses are associated with COVID-19 recovery and protection, but the precise role of T-cell responses remains unclear, and how post-infection vaccination ('hybrid immunity') further augments this immunity To accomplish these goals, we studied healthy adult healthcare workers who were (a) uninfected and unvaccinated (n = 12), (b) uninfected and vaccinated with Pfizer-BioNTech BNT162b2 vaccine (2 doses n = 177, one dose n = 1) or Moderna mRNA-1273 vaccine (one dose, n = 1), and (c) previously infected with SARS-CoV-2 and vaccinated (BNT162b2, two doses, n = 6, one dose n = 1; mRNA-1273 two doses, n = 1). Infection status was determined by repeated PCR testing of participants.

CHARM: COVID-19 Health Action Response for Marines-Association of antigen-specific interferon-gamma and IL2 responses with asymptomatic and symptomatic infections after a positive qPCR SARS-CoV-2 test.

SARS-CoV-2 T cell responses are associated with COVID-19 recovery, and Class I- and Class II-restricted epitopes have been identified in the spike (S), nucleocapsid (N) and membrane (M) proteins and others. This prospective COVID-19 Health Action Response for Marines (CHARM) study enabled assessment of T cell responses against S, N and M proteins in symptomatic and asymptomatic SARS-CoV-2 infected participants. At enrollment all participants were negative by qPCR; follow-up occurred biweekly and bimonthly for the next 6 weeks.

Towards large-scale identification of HLA-restricted T cell epitopes from four vaccine candidate antigens in a malaria endemic community in Ghana.

Sterile protection against clinical malaria has been achieved in animal models and experimental human challenge studies involving immunization with radiation attenuated Plasmodium falciparum sporozoite vaccines as well as by live sporozoites under chloroquine prophylaxis. Parasite-specific IFN-γ and granzyme B-secreting CD8 + T cells have been identified as key mediators of protection. Although the exact parasite targets of protective CD8 + T cell responses are not fully defined, responses against a handful of vaccine candidate antigens have been associated with protection.

A phase IIA extension study evaluating the effect of booster vaccination with a fractional dose of RTS,S/AS01 in a controlled human malaria infection challenge.

Background: We previously demonstrated that RTS,S/AS01 and RTS,S/AS01 vaccination regimens including at least one delayed fractional dose can protect against Plasmodium falciparum malaria in a controlled human malaria infection (CHMI) model, and showed inferiority of a two-dose versus three-dose regimen. In this follow-on trial, we evaluated whether fractional booster vaccination extended or induced protection in previously protected (P-Fx) or non-protected (NP-Fx) participants.

Methods: 49 participants (P-Fx: 25; NP-Fx: 24) received a fractional (1/5th dose-volume) RTS,S/AS01 booster 12 months post-primary regimen.

Comparison of the impact of allelic polymorphisms in PfAMA1 on the induction of T Cell responses in high and low malaria endemic communities in Ghana.

Background: Malaria eradication requires a combined effort involving all available control tools, and these efforts would be complemented by an effective vaccine. The antigen targets of immune responses may show polymorphisms that can undermine their recognition by immune effectors and hence render vaccines based on antigens from a single parasite variant ineffective against other variants. This study compared the influence of allelic polymorphisms in Plasmodium falciparum apical membrane antigen 1 (PfAMA1) peptide sequences from three strains of P.

Comparative analysis of the ex vivo IFN-gamma responses to CD8+ T cell epitopes within allelic forms of PfAMA1 in subjects with natural exposure to malaria.

Antigen polymorphisms in essential malarial antigens are a key challenge to the design and development of broadly effective malaria vaccines. The effect of polymorphisms on antibody responses is fairly well studied while much fewer studies have assessed this for T cell responses. This study investigated the effect of allelic polymorphisms in the malarial antigen apical membrane antigen 1 (AMA1) on ex vivo T cell-specific IFN-γ responses in subjects with lifelong exposure to malaria.

A three-antigen Plasmodium falciparum DNA prime-Adenovirus boost malaria vaccine regimen is superior to a two-antigen regimen and protects against controlled human malaria infection in healthy malaria-naïve adults.

Background: A DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encoding Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in 4/15 (27%) of subjects against controlled human malaria infection (CHMI) that was statistically associated with CD8+ T cell responses. Subjects with high level pre-existing immunity to HuAd5 were not protected, suggesting an adverse effect on vaccine efficacy (VE). We replaced HuAd5 with chimpanzee adenovirus 63 (ChAd63), and repeated the study, assessing both the two-antigen (CSP, AMA1 = CA) vaccine, and a novel three-antigen (CSP, AMA1, ME-TRAP = CAT) vaccine that included a third pre-erythrocytic stage antigen [malaria multiple epitopes (ME) fused to the Pf thrombospondin-related adhesive protein (TRAP)] to potentially enhance protection.

IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS.

Background: Immunization with radiation-attenuated sporozoites (RAS) by mosquito bites provides >90% sterile protection against Plasmodium falciparum malaria in humans. We conducted a clinical trial based on data from previous RAS clinical trials that suggested that 800-1200 infected bites should induce ~50% protective vaccine efficacy (VE) against controlled human malaria infection (CHMI) administered three weeks after the final immunization. Two cohorts were immunized separately.

Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice.

Human malaria affects the vast majority of the world's population with the Plasmodium falciparum species causing the highest rates of morbidity and mortality. With no licensed vaccine and leading candidates achieving suboptimal protection in the field, the need for an effective immunoprophylactic option continues to motivate the malaria research community to explore alternative technologies. Recent advances in the mRNA discipline have elevated the long-neglected platform to the forefront of infectious disease research.

An open label study of the safety and efficacy of a single dose of weekly chloroquine and azithromycin administered for malaria prophylaxis in healthy adults challenged with 7G8 chloroquine-resistant Plasmodium falciparum in a controlled human malaria infection model.

Background: Malaria remains the top infectious disease threat facing the U.S. military in many forward operating environments.

Multidose Priming and Delayed Boosting Improve Plasmodium falciparum Sporozoite Vaccine Efficacy Against Heterologous P. falciparum Controlled Human Malaria Infection.

Background: A live-attenuated Plasmodium falciparum sporozoite (SPZ) vaccine (PfSPZ Vaccine) has shown up to 100% protection against controlled human malaria infection (CHMI) using homologous parasites (same P. falciparum strain as in the vaccine). Using a more stringent CHMI, with heterologous parasites (different P.

A Phase IIa Controlled Human Malaria Infection and Immunogenicity Study of RTS,S/AS01E and RTS,S/AS01B Delayed Fractional Dose Regimens in Malaria-Naive Adults.

Background: A previous RTS,S/AS01B vaccine challenge trial demonstrated that a 3-dose (0-1-7-month) regimen with a fractional third dose can produce high vaccine efficacy (VE) in adults challenged 3 weeks after vaccination. This study explored the VE of different delayed fractional dose regimens of adult and pediatric RTS,S/AS01 formulations.

Methods: A total of 130 participants were randomized into 5 groups.

IMRAS-A clinical trial of mosquito-bite immunization with live, radiation-attenuated P. falciparum sporozoites: Impact of immunization parameters on protective efficacy and generation of a repository of immunologic reagents.

Background: Immunization with radiation-attenuated sporozoites (RAS) by mosquito bite provides >90% sterile protection against Plasmodium falciparum (Pf) malaria in humans. RAS invade hepatocytes but do not replicate. CD8+ T cells recognizing parasite-derived peptides on the surface of infected hepatocytes are likely the primary protective mechanism.

Novel malaria antigen Plasmodium yoelii E140 induces antibody-mediated sterile protection in mice against malaria challenge.

Only a small fraction of the antigens expressed by malaria parasites have been evaluated as vaccine candidates. A successful malaria subunit vaccine will likely require multiple antigenic targets to achieve broad protection with high protective efficacy. Here we describe protective efficacy of a novel antigen, Plasmodium yoelii (Py) E140 (PyE140), evaluated against P.

Identification of Plasmodium falciparum circumsporozoite protein-specific CD8+ T cell epitopes in a malaria exposed population.

Background: Sterile protection against malaria, most likely mediated by parasite-specific CD8+ T cells, has been achieved by attenuated sporozoite vaccination of animals as well as malaria-naïve and malaria-exposed subjects. The circumsporozoite protein (CSP)-based vaccine, RTS,S, shows low efficacy partly due to limited CD8+ T cell induction, and inclusion of such epitopes could improve RTS,S. This study assessed 8-10mer CSP peptide epitopes, present in predicted or previously positive P.

Antibody-Dependent, Gamma Interferon-Independent Sterilizing Immunity Induced by a Subunit Malaria Vaccine.

The development of effective malaria vaccines is hampered by incomplete understanding of the immunological correlates of protective immunity. Recently, the moderate clinical efficacy of the circumsporozoite protein (CSP)-based RTS,S/AS01 vaccine in phase 3 studies highlighted the urgency to design and test more efficacious next-generation malaria vaccines. In this study, we report that immunization with recombinant CSP from (rCSP), when delivered in Montanide ISA 51, induced sterilizing immunity against sporozoite challenge in C57BL/6 and BALB/c strains of mice.

Antigenicity and immune correlate assessment of seven Plasmodium falciparum antigens in a longitudinal infant cohort from northern Ghana.

The current global malaria control and elimination agenda requires development of additional effective disease intervention tools. Discovery and characterization of relevant parasite antigens is important for the development of new diagnostics and transmission monitoring tools and for subunit vaccine development. This study assessed the natural antibody response profile of seven novel Plasmodium falciparum pre-erythrocytic antigens and their potential association with protection against clinical malaria.

T-cell responses against Malaria: Effect of parasite antigen diversity and relevance for vaccine development.

The on-going agenda for global malaria elimination will require the development of additional disease control and prevention measures since currently available tools are showing signs of inadequacy. Malaria vaccines are seen as one such important addition to the control arsenal since vaccines have proven to be highly effective public health tools against important human diseases. Both cell-mediated and antibody responses are generally believed to be important for malaria parasite control, although the exact targets of T and B cell responses against malaria have not been clearly defined.

Profiling the Targets of Protective CD8 T Cell Responses to Infection.

T cells are critical effectors of host immunity that target intracellular pathogens, such as the causative agents of HIV, tuberculosis, and malaria. The development of vaccines that induce effective cell-mediated immunity against such pathogens has proved challenging; for tuberculosis and malaria, many of the antigens targeted by protective T cells are not known. Here, we report a novel approach for screening large numbers of antigens as potential targets of T cells.

New gorilla adenovirus vaccine vectors induce potent immune responses and protection in a mouse malaria model.

Background: A DNA-human Ad5 (HuAd5) prime-boost malaria vaccine has been shown to protect volunteers against a controlled human malaria infection. The potency of this vaccine, however, appeared to be affected by the presence of pre-existing immunity against the HuAd5 vector. Since HuAd5 seroprevalence is very high in malaria-endemic areas of the world, HuAd5 may not be the most appropriate malaria vaccine vector.