•New interventions, including vaccines, needed to prevent disease and accelerate elimination.•Biological feasibility, for multiple vaccines approaches, has been demonstrated.•Identification of ...biomarkers of protection needed to further accelerate progress.•Building on success of RTS,S is a leading next-generation vaccine development strategy.•Heavy reliance on public and philanthropic funding expected to continue.
Despite recent progress in reducing deaths attributable to malaria, it continues to claim approximately 500,000 lives per year and is associated with approximately 200 million infections. New tools, including safe and effective vaccines, are needed to ensure that the gains of the last 15 years are leveraged toward achieving the ultimate goal of malaria parasite eradication. In 2015, the European Medicines Agency announced the adoption of a positive opinion for the malaria vaccine candidate most advanced in development, RTS,S/AS01, which provides modest protection against clinical malaria; in early 2016, WHO recommended large-scale pilot implementations of RTS,S in settings of moderate-to-high malaria transmission. In alignment with these advancements, the community goals and preferred product characteristics for next-generation vaccines have been updated to inform the development of vaccines that are highly efficacious in preventing clinical malaria, and those needed to accelerate parasite elimination. Next-generation vaccines, targeting all stages of the parasite lifecycle, are in early-stage development with the most advanced in Phase 2 trials. Importantly, progress is being made in the definition of feasible regulatory pathways to accelerate timelines, including for vaccines designed to interrupt transmission of parasites from humans to mosquitoes. The continued absence of financially lucrative, high-income markets to drive investment in malaria vaccine development points to continued heavy reliance on public and philanthropic funding.
Abstract Despite impressive gains over the last 15 years in reducing the mortality associated with malaria, it remains a public health emergency. New interventions, such as vaccines, are needed to ...ensure that previous gains serve as a foundation for future progress. Vaccines have the potential to prevent severe disease and death in those most vulnerable, and to accelerate elimination and eradication by breaking the cycle of parasite transmission. The pipeline is as healthy as it has ever been, with approaches targeting different stages of the parasite lifecycle using an array of technologies. This article reviews recent progress and reviews key considerations in the quest to develop products that are aligned with the unmet medical need.
Highlights ► Community vision is to eliminate and eventually eradicate malaria. ► Vaccine development goals need to be aligned with this vision. ► Vaccines to prevent clinical disease and interrupt ...transmission are needed. ► Breakthroughs, challenges and opportunities for vaccines are reviewed.
Background. Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, ...including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologie responses. Methods. In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (FxO17M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. Results. A total of 26 of 30 subjects in the FxO17M group (vaccine efficacy VE, 86.7% 95% confidence interval CI, 66.8%-94.6%; P<.0001) and 10 of 16 in the 012M group (VE, 62.5% 95% CI, 29.4%-80.1%; P=.0009) were protected against infection, and protection differed between schedules (P=.040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. Discussions. A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. Clinical Trials Registration. NCT01857869.
Abstract New interventions are needed to reduce morbidity and mortality associated with malaria, as well as to accelerate elimination and eventual eradication. Interventions that can break the cycle ...of parasite transmission, and prevent its reintroduction, will be of particular importance in achieving the eradication goal. In this regard, vaccines that interrupt malaria transmission (VIMT) have been highlighted as an important intervention, including transmission-blocking vaccines that prevent human-to-mosquito transmission by targeting the sexual, sporogonic, or mosquito stages of the parasite (SSM-VIMT). While the significant potential of this vaccine approach has been appreciated for decades, the development and licensure pathways for vaccines that target transmission and the incidence of infection, as opposed to prevention of clinical malaria disease, remain ill-defined. This article describes the progress made in critical areas since 2010, highlights key challenges that remain, and outlines important next steps to maximize the potential for SSM-VIMTs to contribute to the broader malaria elimination and eradication objectives.
Malaria, one of the most common vector borne human diseases, is a major world health issue. In 2015 alone, more than 200 million people were infected with malaria, out of which, 429 000 died. Even ...though artemisinin-based combination therapies (ACT) are highly effective at treating malaria infections, novel efforts toward development of vaccines to prevent transmission are still needed. Pfs25, a postfertilization stage parasite surface antigen, is a leading transmission-blocking vaccine (TBV) candidate. It is postulated that Pfs25 anchors to the cell membrane using a glycosylphosphatidylinositol (GPI) linker, which itself possesses pro-inflammatory properties. In this study, Escherichia coli derived extract (XtractCF+TM) was used in cell free protein synthesis CFPS to successfully express >200 mg/L of recombinant Pfs25 with a C-terminal non-natural amino acid (nnAA), namely, p-azidomethyl phenylalanine (pAMF), which possesses a reactive azide group. Thereafter, a unique conjugate vaccine (CV), namely, Pfs25-GPI was generated with dibenzocyclooctyne (DBCO) derivatized glycan core of malaria GPI using a simple but highly efficient copper free click chemistry reaction. In mice immunized with Pfs25 or Pfs25-GPI, the Pfs25-GPI group showed significantly higher titers compared to the Pfs25 group. Moreover, only purified IgGs from Pfs25-GPI group were able to significantly block transmission of parasites to mosquitoes, as judged by a standard membrane feeding assay SMFA. To our knowledge, this is the first report of the generation of a CV using Pfs25 and malaria specific GPI where the GPI is shown to enhance the ability of Pfs25 to elicit transmission blocking antibodies.
The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of ...malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.
Background. Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept ...phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point. Methods. Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data. Results. FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine- or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR. Conclusions. FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates. Clinical Trials Registration. NCT02044198.
Remarkable progress has been made in coordinated malaria control efforts with substantial reductions in malaria-associated deaths and morbidity achieved through mass administration of drugs and ...vector control measures including distribution of long-lasting insecticide-impregnated bednets and indoor residual spraying. However, emerging resistance poses a significant threat to the sustainability of these interventions. In this light, the malaria research community has been charged with the development of a highly efficacious vaccine to complement existing malaria elimination measures. As the past 40 years of investment in this goal attests, this is no small feat. The malaria parasite is a highly complex organism, exquisitely adapted for survival under hostile conditions within human and mosquito hosts. Here we review current vaccine strategies to accelerate elimination and the potential for novel and innovative approaches to vaccine design through a better understanding of the host-parasite interaction.
For some diseases, successful vaccines have been developed using a nonpathogenic counterpart of the causative microorganism of choice. The nonpathogenicity of the rodent
(
) parasite in humans ...prompted us to evaluate its potential as a platform for vaccination against human infection by
(
), a causative agent of malaria. We hypothesized that the genetic insertion of a leading protein target for clinical development of a malaria vaccine,
circumsporozoite protein (CSP), in its natural pre-erythrocytic environment, would enhance
's capacity to induce protective immunity against
infection. Hence, we recently generated a transgenic
sporozoite immunization platform expressing
CSP (
Vac), and we now report the clinical evaluation of its biological activity against controlled human malaria infection (CHMI). This first-in-human trial shows that
Vac is safe and well tolerated, when administered by a total of ~300
Vac-infected mosquitoes per volunteer. Although protective efficacy evaluated by CHMI showed no sterile protection at the tested dose, significant delays in patency (2.2 days,
= 0.03) and decreased parasite density were observed after immunization, corresponding to an estimated 95% reduction in
liver parasite burden (confidence interval, 56 to 99%;
= 0.010).
Vac elicits dose-dependent cross-species cellular immune responses and functional
CSP-dependent antibody responses that efficiently block
sporozoite invasion of liver cells in vitro. This study demonstrates that
Vac immunization elicits a marked biological effect, inhibiting a subsequent infection by the human
parasite, and establishes the clinical validation of a new paradigm in malaria vaccination.
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