Biology subjects

Drew, D. R.

Publications and source records attributed to Drew, D. R..

4 recordsLinked to original sources

bioRxiv2024

IgM plays a prominent role in naturally acquired immunity against Plasmodium falciparum gametocytes

The development of transmission-blocking vaccines against Plasmodium falciparum malaria could facilitate malaria elimination. However, limitations in the knowledge of the human immune responses against P. falciparum transmission stages, known as gametocytes, represent a critical roadblock to vaccine development. We evaluated human antibodies acquired through natural malaria exposure to whole gametocytes and recombinant antigens expressed by transmission stages, including the major transmission-blocking vaccine candidates Pfs230 and Pfs48/45 and other transmission stages, Pf38, Pf12 and Pf41. Among individuals residing in Kenya and Papua New Guinea, we found substantial antibody responses to whole gametocytes and to all recombinant transmission stage antigens with high levels of IgG, IgG subclasses and IgM. Complement fixation by antibodies to gametocytes is key for effective transmission-blocking activity. We found that purified IgM was substantially more potent than IgG at mediating complement fixation and activation. Higher antibody levels were generally observed in individuals positive for P. falciparum infection, including gametocyte positive individuals, and these antibodies generally increased with age. Our findings reveal that IgM is a prominent feature of antibody responses to gametocytes and that antibodies target multiple antigens. The further demonstration that IgM has high functional activity against gametocytes suggests IgM plays an important role in immunity to transmission stages. Our data provide new insights to inform the development of potent transmission-blocking vaccines.

immunology↗

bioRxiv2020

Novel virus-like particle vaccine encoding the circumsporozoite protein of Plasmodium falciparum is immunogenic and induces functional antibody responses

RTS,S is the leading malaria vaccine in development, but has demonstrated only moderate protective efficacy in clinical trials. RTS,S is a virus-like particle (VLP) that uses the human hepatitis B virus as scaffold to display the malaria sporozoite antigen, circumsporozoite protein (CSP). Particle formation requires fourfold excess scaffold antigen, and as a result, CSP represents only a small portion of the final vaccine construct. Alternative VLP or nanoparticle platforms that reduce the amount of scaffold antigen and increase the amount of the target CSP antigen present in particles may enhance vaccine immunogenicity and efficacy. Here, we describe the production and characterization of a novel VLP that uses the small surface antigen (dS) of duck hepatitis B virus to display CSP. The CSP-dS fusion protein successfully formed VLPs without the need for excess scaffold antigen, and thus CSP represented a larger portion of the vaccine construct. Importantly, this is the first report of a dS-based vaccine that formed particles without excess scaffold protein. CSP-dS formed large particles approximately 31-74 nm in size and were confirmed to display CSP on the surface. The CSP-dS VLP was highly immunogenic in mice and induced antibodies to multiple regions of CSP, even when administered at a lower vaccine dosage. Vaccine-induced antibodies demonstrated functional activity, including the ability to interact with complement and Fc{gamma}-receptors, both previously identified as important in malaria immunity. Our novel platform to produce VLPs without excess scaffold protein has wide implications for the future development of innovative vaccines for malaria and other infectious diseases.

immunology↗

bioRxiv2019

Multi-functional antibodies are induced by the RTS,S malaria vaccine and associated with protection in a phase I/IIa trial

BackgroundRTS,S is the leading malaria vaccine candidate, but only confers partial efficacy against malaria in children. RTS,S is based on the major Plasmodium falciparum sporozoite surface antigen, circumsporozoite protein (CSP). The induction of anti-CSP antibodies is important for protection, however, it is unclear how protective antibodies function. MethodsWe quantified the induction of functional anti-CSP antibody responses in healthy malaria-naive adults (N=45) vaccinated with RTS,S/AS01. This included the ability to mediate effector functions via the fragment crystallizable (Fc) region, such as interacting with human complement proteins and Fc{gamma}-receptors (Fc{gamma}Rs) that are expressed on immune cells, which promote various immunological functions. ResultsOur major findings were i) RTS,S-induced antibodies mediate Fc-dependent effector functions, ii) functional antibodies were generally highest after the second vaccine dose; iii) functional antibodies targeted multiple regions of CSP, iv) participants with higher levels of functional antibodies had a reduced probability of developing parasitemia following homologous challenge (p<0.05); v) non-protected subjects had higher levels of anti-CSP IgM. ConclusionsOur data suggests a role for Fc-dependent antibody effector functions in RTS,S-induced immunity. Enhancing the induction of these functional activities may be a strategy to improve the protective efficacy of RTS,S or other malaria vaccines.

immunology↗

bioRxiv2019

Malaria vaccine candidates displayed on novel virus-like particles are immunogenic and induce transmission-blocking activity

The development of effective malaria vaccines remains a global health priority. Currently, the most advanced vaccine, known as RTS,S, has only shown modest efficacy in clinical trials. Thus, the development of more efficacious vaccines by improving the formulation of RTS,S for increased efficacy or to interrupt malaria transmission are urgently needed. The RTS,S vaccine is based on the presentation of a fragment of the sporozoite antigen on the surface of virus-like particles (VLPs) based on human hepatitis B virus (HBV). In this study, we have developed and evaluated a novel VLP platform based on duck HBV (known as Metavax) for malaria vaccine development. This platform can incorporate large and complex proteins into VLPs and is produced in a Hansenula cell line compatible with cGMP vaccine production. Here, we have established the expression of leading P. falciparum malaria vaccine candidates as VLPs. This includes Pfs230 and Pfs25, which are candidate transmission-blocking vaccine antigens. We demonstrated that the VLPs effectively induce antibodies to malaria vaccine candidates with minimal induction of antibodies to the duck-HBV scaffold antigen. Antibodies to Pfs230 also recognised native protein on the surface of gametocytes, and antibodies to both Pfs230 and Pfs25 demonstrated transmission-reducing activity in standard membrane feeding assays. These results establish the potential utility of this VLP platform for malaria vaccines, which may be suitable for the development of multi-component vaccines that achieve high vaccine efficacy and transmission-blocking immunity.

immunology↗