Introduction and Background of the Project

Introduction

The world’s first malaria vaccine, RTS,S/AS01, is a recombinant VLP containing truncated CSP as the target antigen and formulated with a TLR4/QS21-containing adjuvant (AS01). In a large multi-center Phase 3 trial RTS,S/AS01 demonstrated a ~40% reduction in clinical malaria incidence in young African children, over ~4 years of follow-up, and is currently undergoing pilot implementation in 3 African countries. A next generation malaria vaccine with improved efficacy and durability offers the potential for even greater public health impact.

Project objective

The overall objective of T2020-252 project is to rigorously test a novel vaccine candidate, flCSP/SA-1, comprised of a full-length recombinant CSP adjuvanted with a novel toll-like receptor 7 (TLR7) agonist, SA-1, for superiority to the RTS,S/AS01 benchmark vaccine, to inform whether to advance flCSP/SA-1 to preclinical development.  We will examine two aspects of the vaccine, adjuvant (SA-1 vs AS01) and antigen (flCSP vs RTS,S), independently and in parallel.

Our specific objectives are:

1. Test whether flCSP/SA-1, compared to flCSP/AS01, for induction of improved durability of antibody responses in NHP model.  NHPs are used as the test species because rodents do not adequately model the rapid decline of antibody titer observed with RTS,S/AS01 in humans.

2. Test whether flCSP antigen, compared to RTS,S, for induction of stronger protective efficacy in well qualified rodent challenge model.

Project design

Activity 1. Evaluate antibody response durability in NHP model. Cynomolgus monkeys will be used as the primary animal model for immunogenicity because of their responsiveness to the TLR7 agonist in SA-1 and the similarity of induced functional antibody pharmacokinetics (PK) seen in humans. Monkeys will be immunized with of flCSP formulated with SA-1 or with AS01. 

Activity 2.1. Evaluate protective efficacy of antibodies induced by flCSP/AS01 and by RTS,S/AS01.  We will next compare the quality of the antibody response induced by flCSP or by RTS,S. Each immunogen will be tested in the same adjuvant, AS01, which is known to be active in mice. The experimental design will be closely based on our previously published qualification of in vivo models.

Activity 2.2. Evaluate protective efficacy induced by flCSP/SA-1.  To assure that the combination of flCSP with SA-1 adjuvant results in protective efficacy in the mouse model, we will conduct active immunization followed by challenge with sporozoites and measure protection from parasitemia.

At completion of T2020-252 we will conduct a Go/no go decision to recommend preclinical development of flCSP/SA-1. A go decision will require evidence of superior, durable protection.

How can your partnership (project) address global health challenges?

New tools are urgently needed to help control malaria and to support future elimination and eventual eradication efforts.

A vaccine that effectively prevents infection, across all ages, has the potential to accelerate regional elimination and eventual eradication efforts. Modeling studies show that durability of protection, along with coverage, is key to impacting the infection prevalence critical to elimination efforts. For this reason, we focus T2020-252 on development of a next-generation vaccine with the potential to deliver the durable protection. Further, results from animal models show that a combination vaccine that blocks both human infection (as described here) and transmission to mosquitoes (work in progress under the GHIT award PD G2019-205) will be synergistically effective.

What sort of innovation are you bringing in your project?

The T2020-252 combines experience with innovation to seek solutions for the challenge of design and development of a next generation malaria vaccine. PATH brings decades of experience in the development of RTS,S/AS01 and combines this with innovative insights into what will be required to achieve durable protection in a new vaccine. Sumitomo Dainippon Pharma provides a pharmaceutical company perspective for drug development and contributes the SA-1 adjuvant technology platform designed to exploit a novel mode of action, TLR7 activation. Ehime University provides many years of experience in malaria parasite biology and puts this to use for the implementation of a novel assay for function of vaccine induced antibody responses. Together the T2020-252 partnership combines innovative approaches with risk mitigation through extensive relevant experience.

Role and Responsibility of Each Partner

PATH is the primary applicant and will be responsible for the overall conduct and reporting of the proposed work. PATH will provide the flCSP recombinant antigen to Sumitomo Dainippon Pharma and Ehime University. PATH will also pursue agreements that enable the use of RTS,S/AS01 as a benchmark. 

Sumitomo Dainippon Pharma will be responsible for providing the SA-1 adjuvant and conducting the NHP study as described in objective 1.  

Ehime University will be responsible for evaluation of vaccine-induced protective efficacy in rodent challenge models.

Others (including references if necessary)

References available in the T2020-252 application. 

WHO Global Technical Strategy for Malaria 2016-2030. https://www.who.int/malaria/publications/atoz/9789241564991/en/

WHO World Malaria Report 2020. https://www.who.int/malaria/publications/world-malaria-report-2020/en/

Final Report

1. Project objective

With a goal to develop a second-generation vaccine against P. falciparum malaria, the project has two specific objectives:

• To evaluate whether flCSP/SA-1, compared to flCSP/AS01, induces improved durability of antibody responses in a non-human-primate (NHP) model. 
• To evaluate whether flCSP (a soluble recombinant protein), compared to RTS,S (a virus-like-particle VLP), induces antibodies of stronger protective efficacy in a well-qualified rodent challenge model.

2. Project design

• Cynomolgus monkeys were selected to assess response durability induced by flCSP/SA-1, flCSP/AS01, or RTS,S/AS01. Anti-flCSP and anti-NANP antibody responses were followed for a total of 40 weeks.
• Mice and rabbits were used to compare the quality of the antibody response induced by flCSP or by RTS,S. IgGs purified from sera in animals immunized with flCSP/AS01 or RTS,S/AS01 were passively transferred to mice followed by challenge with a transgenic P. berghei parasite expressing P. falciparum CSP (PbPfCSP). In the mouse challenge model, the overall protective efficacy of flCSP/SA-1 and RTS,S/AS01 was also evaluated by active immunization of the test vaccines.

3. Results, lessons learned

We achieved both milestones as described below:

Milestone 1. Tech Platform ID Completed: NHP study completed and antibody durability induced by flCSP/SA-1 and flCSP/AS01 measured and analyzed. The half-life values of anti-flCSP IgG induced by flCSP/SA-1 are longer than flCSP/AS01, whereas the peak antibody titers were comparable in cynomolgus monkeys. RTS,S/AS01 induced the highest antibody levels.

Milestone 2. Antigen identified, research completed: Completed comparison of flCSP vs RTS,S in AS01 adjuvant, demonstrated protective immunity induced by flCSP/SA-1 in mouse challenge model. In both mice and rabbits, RTS,S/AS01 induced higher antibody titers than those conferred by flCSP/AS01. Both mouse and rabbit immune IgGs induced by RTS,S/AS01 significantly reduced parasite liver burden compared to a naive IgG control in the mouse challenge model. Only mouse immune IgGs induced by flCSP/AS01 reduced parasite liver burden, whereas rabbit immune IgGs did not, due to low antibody titers. The benchmark vaccine RTS,S/AS01 induced higher antibody titers and conferred stronger inhibition from parasite liver burden than flCSP/SA-1 in the active immunized mouse challenge model.

In this study, SA-1 adjuvant induced longer IgG half-life than AS01 when formulated with flCSP. The RTS,S antigen induced higher IgG titers than flCSP. RTS,S/AS01 was more protective in the mouse challenge model as compared to flCSP/SA-1.