- Email: [email protected]
PfRH5 vaccine efficacy against heterologous strain blood-stage Plasmodium falciparum
Poster Abstracts
PfRH5 vaccine efficacy against heterologous strain bloodstage Plasmodium falciparum Alexander D Douglas, G Christian Baldeviano, Kazutoyo Miura, Gavin J Wright, Simon J Draper
Abstract Background There is a need for a more effective vaccine against Plasmodium falciparum than the current leading candidate, RTS,S. Vaccines against the parasite’s asexual blood-stage might reduce mortality, morbidity, and transmission of malaria, but face problems of antigenic polymorphism and the apparent requirement for exceptionally high antibody concentrations to achieve protection. We recently reported that vaccines based on the blood-stage merozoite antigen PfRH5 induce antibodies capable of strain-transcending in-vitro growth inhibition activity (GIA). Here, we report the results of a study of vaccination of non-human primates followed by challenge with P falciparum. Methods Non-human primates (Aotus nancymaae) were vaccinated with PfRH5 vaccine formulations (including PfRH5 protein in Freund’s adjuvant and an adenovirus/poxvirus viral vector regimen) based on the 3D7 strain of P falciparum, and challenged with the heterologous P falciparum FVO strain. Control animals were given vaccines that did not contain a malaria antigen. The primary vaccine efficacy endpoints were the need for antimalarial treatment compared with historical controls in the PfRH5-Freund’s group; and in the viral vector group, cumulative parasitaemia to day 10 of the study was compared with control animals challenged after receiving vaccines lacking a malaria antigen. As well as vaccine-induced protection against the challenge, antigen-specific antibody concentration, parasite-neutralising antibody (GIA), and cellular immune responses were assessed. Findings Six of six animals vaccinated with PfRH5 in Freund’s adjuvant and four of six animals vaccinated with human-compatible PfRH5 viral vector vaccines survived the challenge without reaching an endpoint requiring treatment, and without clinically evident symptoms of malaria, compared with none of six control animals (p<0·001 for vaccine efficacy in both groups vs controls, Mann-Whitney U test). There was a strong correlation between cumulative parasitaemia to day 10 and both antigen-specific antibody concentration and parasite-neutralising antibody activity (Spearman rank correlation coefficient r=–0·82 and –0·92, respectively; p<0·0001 for both).
Published Online February 26, 2014 Poster 64 Jenner Institute, University of Oxford, Oxford, UK (A D Douglas DPhil, S J Draper DPhil); US Naval Medical Research Unit 6, Lima, Peru (G C Baldeviano PhD); Malaria Immunology Section, NIAID, National Institutes of Health, Bethesda, Maryland, USA (K Miura PhD); and Cell Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge, UK (G J Wright DPhil) Correspondence to: Dr Alexander Douglas, Jenner Institute, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK [email protected]
Interpretation These results are the first, to our knowledge, to show protection against blood-stage malaria by a human-compatible vaccine and the first to show strain-transcending protection in this highly stringent challenge model; furthermore, they show that an antigen selected on the basis of in-vitro neutralisation assays can induce in-vivo protection. PfRH5-based vaccines are now entering clinical development. There is a need to assess the efficacy of these vaccines in man, to assess the longevity of vaccine-induced protection, and to formally assess protection by passively transferred parasite-neutralising antibody. Funding Wellcome Trust, UK Medical Research Council, Isis Innovations. Contributors ADD and SJD designed the study. ADD, GCB, GJW, and KM did experiments. ADD and SJD analysed the data. ADD wrote the abstract. Conflicts of interest ADD, GJW, and SJD are named inventors on patent applications relating to PfRH5-based malaria vaccines. GCB is an employee of the US Government. This work was prepared as part of his official duties. Title 17 U.S.C. §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person’s official duties. The views expressed in this abstract are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. All other authors declare that they have no conflicts of interest.
www.thelancet.com
43
PfRH5 vaccine efficacy against heterologous strain bloodstage Plasmodium falciparum Alexander D Douglas, G Christian Baldeviano, Kazutoyo Miura, Gavin J Wright, Simon J Draper
Abstract Background There is a need for a more effective vaccine against Plasmodium falciparum than the current leading candidate, RTS,S. Vaccines against the parasite’s asexual blood-stage might reduce mortality, morbidity, and transmission of malaria, but face problems of antigenic polymorphism and the apparent requirement for exceptionally high antibody concentrations to achieve protection. We recently reported that vaccines based on the blood-stage merozoite antigen PfRH5 induce antibodies capable of strain-transcending in-vitro growth inhibition activity (GIA). Here, we report the results of a study of vaccination of non-human primates followed by challenge with P falciparum. Methods Non-human primates (Aotus nancymaae) were vaccinated with PfRH5 vaccine formulations (including PfRH5 protein in Freund’s adjuvant and an adenovirus/poxvirus viral vector regimen) based on the 3D7 strain of P falciparum, and challenged with the heterologous P falciparum FVO strain. Control animals were given vaccines that did not contain a malaria antigen. The primary vaccine efficacy endpoints were the need for antimalarial treatment compared with historical controls in the PfRH5-Freund’s group; and in the viral vector group, cumulative parasitaemia to day 10 of the study was compared with control animals challenged after receiving vaccines lacking a malaria antigen. As well as vaccine-induced protection against the challenge, antigen-specific antibody concentration, parasite-neutralising antibody (GIA), and cellular immune responses were assessed. Findings Six of six animals vaccinated with PfRH5 in Freund’s adjuvant and four of six animals vaccinated with human-compatible PfRH5 viral vector vaccines survived the challenge without reaching an endpoint requiring treatment, and without clinically evident symptoms of malaria, compared with none of six control animals (p<0·001 for vaccine efficacy in both groups vs controls, Mann-Whitney U test). There was a strong correlation between cumulative parasitaemia to day 10 and both antigen-specific antibody concentration and parasite-neutralising antibody activity (Spearman rank correlation coefficient r=–0·82 and –0·92, respectively; p<0·0001 for both).
Published Online February 26, 2014 Poster 64 Jenner Institute, University of Oxford, Oxford, UK (A D Douglas DPhil, S J Draper DPhil); US Naval Medical Research Unit 6, Lima, Peru (G C Baldeviano PhD); Malaria Immunology Section, NIAID, National Institutes of Health, Bethesda, Maryland, USA (K Miura PhD); and Cell Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge, UK (G J Wright DPhil) Correspondence to: Dr Alexander Douglas, Jenner Institute, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK [email protected]
Interpretation These results are the first, to our knowledge, to show protection against blood-stage malaria by a human-compatible vaccine and the first to show strain-transcending protection in this highly stringent challenge model; furthermore, they show that an antigen selected on the basis of in-vitro neutralisation assays can induce in-vivo protection. PfRH5-based vaccines are now entering clinical development. There is a need to assess the efficacy of these vaccines in man, to assess the longevity of vaccine-induced protection, and to formally assess protection by passively transferred parasite-neutralising antibody. Funding Wellcome Trust, UK Medical Research Council, Isis Innovations. Contributors ADD and SJD designed the study. ADD, GCB, GJW, and KM did experiments. ADD and SJD analysed the data. ADD wrote the abstract. Conflicts of interest ADD, GJW, and SJD are named inventors on patent applications relating to PfRH5-based malaria vaccines. GCB is an employee of the US Government. This work was prepared as part of his official duties. Title 17 U.S.C. §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person’s official duties. The views expressed in this abstract are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. All other authors declare that they have no conflicts of interest.
www.thelancet.com
43