Safety, Immunogenicity and Efficacy of Prime-Boost Vaccination with ChAd63 and MVA Encoding ME-TRAP against Plasmodium falciparum Infection in Adults in Senegal

Abstract

Malaria transmission is in decline in some parts of Africa, partly due to the scaling up of control measures. If the goal of elimination is to be achieved, additional control measures including an effective and durable vaccine will be required. Studies utilising the prime-boost approach to deliver viral vectors encoding the pre-erythrocytic antigen ME-TRAP (multiple epitope thrombospondin-related adhesion protein) have shown promising safety, immunogenicity and efficacy in sporozoite challenge studies. More recently, a study in Kenyan adults, similar to that reported here, showed substantial efficacy against P. falciparum infection. One hundred and twenty healthy male volunteers, living in a malaria endemic area of Senegal were randomised to receive either the Chimpanzee adenovirus (ChAd63) ME-TRAP as prime vaccination, followed eight weeks later by modified vaccinia Ankara (MVA) also encoding ME-TRAP as booster, or two doses of anti-rabies vaccine as a comparator. Prior to follow-up, antimalarials were administered to clear parasitaemia and then participants were monitored by PCR for malaria infection for eight weeks. The primary endpoint was time-to-infection with P. falciparum malaria, determined by two consecutive positive PCR results. Secondary endpoints included adverse event reporting, measures of cellular and humoral immunogenicity and a meta-analysis of combined vaccine efficacy with the parallel study in Kenyan adults.We show that this pre-erythrocytic malaria vaccine is safe and induces significant immunogenicity, with a peak T-cell response at seven days after boosting of 932 Spot Forming Cells (SFC)/106 Peripheral Blood Mononuclear Cells(PBMC) compared to 57 SFC/ 106 PBMCs in the control group. However, a vaccine efficacy was not observed: 12 of 57 ME-TRAP vaccinees became PCR positive during the intensive monitoring period as compared to 13 of the 58 controls (P = 0.80). This trial confirms that vaccine efficacy against malaria infection in adults may be rapidly assessed using this efficient and cost-effective clinical trial design. Further efficacy evaluation of this vectored candidate vaccine approach in other malaria transmission settings and age-de-escalation into the main target age groups for a malaria vaccine is in progress.

Vaccines against malaria—still a long way to go

“…Multiple rounds of optimization returned a heterologous prime/boost protocol with chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara virus (MVA), respectively. A recent small phase II study with 115 participants in Senegal showed no efficacy of this vaccine, and combined analysis with earlier data from Kenia returned only a small, albeit significant, delay until patency [40].…”

Plasmodium falciparum pre-erythrocytic stage vaccine development

“…Group A (n:28): ChAd63 ME-TRAP increasing the dose from 1 × 10 8 to 5 × 10 10 vp ID (groups 1-4) and from 1 × 10 10 to 2 × 10 11 IM (groups 5-7) Group B (n:26): ChAd63 ME-TRAP, followed at 8 weeks by MVA ME-TRAP and a booster dose for 5 volunteers with ChAd63 ME-TRAP and for 6 volunteers with MVA ME-TRAP NE [116] 36 adults (18-50 years-old) Trial A (n:16): ChAd63 ME-TRAP n:6 1 × 10 10 VP Trial B (n:30): 10 5 × 10 10 VP a the 56 days MVA ME-TRAP 2 × 10 8 by intramuscular route (IM) NE [111] 138 children and infants Gambia 2-6 year-olds Group 1a (n:6): 1 × 10 10 vp ChAd63 ME-TRAP and 1 × 10 8 pfu MVA ME-TRAP Group 1b (n:6): 1 × 10 10 vp ChAd63 ME-TRAP and 2 × 10 8 pfu MVA ME-TRAP Group 1c (n:6): 1 ml HDCRV Group 1d (n:6): 5 × 0 10 vp ChAd63 ME-TRAP and 1 × 10 8 pfu MVA ME-TRAP Group 1e (n:6): 5 × 10 10 vp ChAd63 ME-TRAP and 2 × 10 8 pfu MVA ME-TRAP Group 1f (n:6): 1 ml HDCRV Gambia 5-12 month-olds Group 2a (n:12): 1 × 10 10 vp ChAd63 ME-TRAP and 1 × 10 8 pfu MVA ME-TRAP Group 2b (n:12): 5 × 10 10 vp ChAd63 ME-TRAP and 1 × 10 10 pfu MVA ME-TRAP Group 2c (n:12): No vaccine Gambia 10 week-olds Group 3a (n:12): 1 × 10 10 vp ChAd63 ME-TRAP and 1 × 10 8 pfu MVA ME-TRAP Group 3b (n:12): 5 × 10 10 vp ChAd63 ME-TRAP and 1 × 10 8 pfu MVA ME-TRAP Group 3c (n:12): No vaccine Burkina Faso (n.30) 5-17 month-olds 5 × 10 10 vp ChAd63 ME-TRAP and 1 × 10 8 pfu MVA ME-TRAP NE [110] Chad63 MVA ME-TRAP (Phase II) 120 adults (18-50 years-old) n. 120 ChAd63 ME-TRAP (5 × 10 5 vp) after 8 weeks n. 60 cases: MVA ME-TRAP (2 × 10 8 pfu) n. 60 controls: anti-rabies vaccine (0.5 ml) 8% adjusted efficacy: 50% (PCR positivity: more than 10 parasites per μl) [117] 120 adults (18-50 years-old) n. 120 ChAd63 ME-TRAP (5 × 10 5 vp) after 8 weeks n. 60 cases: MVA ME-TRAP (2 × 10 8 pfu) n. 60 controls: anti-rabies vaccine (0.5 ml) 67% (PCR positivity: more than 10 parasites per μl) [118] although CD4 + and CD8 + T-cell responses did not increase, being limited after the second and third immunization [23].…”

“…A trial involving adults in Senegal [117] to assess vaccine efficacy using a polymerase chain reaction (PCR) assay was able to detect > 10 parasites/μl blood. PCR was positive for 12 out of 57 participants vaccinated with ChAd63 ME-TRAP with a booster dose of MVA ME-TRAP and 13 out of 58 control patients who received an anti-rabies vaccine were positive by PCR, giving 8% efficacy (which was not statistically significant).…”

“…PCR was positive for 12 out of 57 participants vaccinated with ChAd63 ME-TRAP with a booster dose of MVA ME-TRAP and 13 out of 58 control patients who received an anti-rabies vaccine were positive by PCR, giving 8% efficacy (which was not statistically significant). They thus grouped the results with the 67% efficacy obtained in a study in Kenya and, using Cox regression, showed 50% overall vaccine efficacy in both populations [117,118].…”

Novel viral vectors in infectious diseases

“…This vector was assessed with and without an MVA booster dose, and was found to elicit strong antibody and T‐cell responses, which could be increased in magnitude and durability by an MVA boost. Another chimpanzee adenoviral vector, ChAd63, has also been evaluated in several clinical trials (malaria, leishmaniasis) with results showing excellent safety and immunogenicity, even in infants and children.…”