Malaria transmission-blocking conjugate vaccine in ALFQ adjuvant induces durable functional immune responses in rhesus macaques

AbstractMalaria transmission-blocking vaccines candidates based on Pfs25 and Pfs230 have advanced to clinical studies. Exoprotein A (EPA) conjugate of Pfs25 in Alhydrogel® developed functional immunity in humans, with limited durability. Pfs230 conjugated to EPA (Pfs230D1-EPA) with liposomal adjuvant AS01 is currently in clinical trials in Mali. Studies with these conjugates revealed that non-human primates are better than mice to recapitulate the human immunogenicity and functional activity. Here, we evaluated the effect of ALFQ, a liposomal adjuvant consisting of TLR4 agonist and QS21, on the immunogenicity of Pfs25-EPA and Pfs230D1-EPA in Rhesus macaques. Both conjugates generated strong antibody responses and functional activity after two vaccinations though activity declined rapidly. A third vaccination of Pfs230D1-EPA induced functional activity lasting at least 9 months. Antibody avidity increased with each vaccination and correlated strongly with functional activity. IgG subclass analysis showed induction of Th1 and Th2 subclass antibody levels that correlated with activity.

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Structural vaccinology of malaria transmission-blocking vaccines

Expert Review of Vaccines ◽

10.1080/14760584.2021.1873135 ◽

2021 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Palak N. Patel ◽

Niraj Tolia

Keyword(s):

Malaria Transmission ◽

Transmission Blocking ◽

Structural Vaccinology ◽

Transmission Blocking Vaccines

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Malaria transmission-blocking vaccines: wheat germ cell-free technology can accelerate vaccine development

Expert Review of Vaccines ◽

10.1080/14760584.2019.1674145 ◽

2019 ◽

Vol 18 (10) ◽

pp. 1017-1027

Author(s):

Kazutoyo Miura ◽

Mayumi Tachibana ◽

Eizo Takashima ◽

Masayuki Morita ◽

Bernard N. Kanoi ◽

...

Keyword(s):

Germ Cell ◽

Malaria Transmission ◽

Wheat Germ ◽

Vaccine Development ◽

Transmission Blocking ◽

Transmission Blocking Vaccines

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Plasmodium falciparum gametocyte transit through the cutaneous microvasculature: A new target for malaria transmission blocking vaccines?

Human Vaccines & Immunotherapeutics ◽

10.1080/21645515.2016.1183076 ◽

2016 ◽

Vol 12 (12) ◽

pp. 3189-3195 ◽

Cited By ~ 10

Author(s):

Christian P. Nixon

Keyword(s):

Plasmodium Falciparum ◽

Malaria Transmission ◽

Transmission Blocking ◽

Transmission Blocking Vaccines

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No evidence for positive selection at two potential targets for malaria transmission-blocking vaccines in Anopheles gambiae s.s

Infection Genetics and Evolution ◽

10.1016/j.meegid.2013.01.006 ◽

2013 ◽

Vol 16 ◽

pp. 87-92 ◽

Cited By ~ 2

Author(s):

Jacob E. Crawford ◽

Susan M. Rottschaefer ◽

Boubacar Coulibaly ◽

Madjou Sacko ◽

Oumou Niaré ◽

...

Keyword(s):

Positive Selection ◽

Anopheles Gambiae ◽

Malaria Transmission ◽

Anopheles Gambiae S.S ◽

Transmission Blocking ◽

Transmission Blocking Vaccines

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Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice

10.1101/2020.11.19.20234922 ◽

2020 ◽

Author(s):

Sara A. Healy ◽

Charles Anderson ◽

Bruce J. Swihart ◽

Agnes Mwakingwe ◽

Erin E. Gabriel ◽

...

Keyword(s):

Functional Activity ◽

Rhesus Macaques ◽

Significant Activity ◽

Transmission Blocking ◽

Link Type ◽

Membrane Feeding ◽

Antibody Titers ◽

Human Immune Response ◽

Reducing Activity ◽

Transmission Blocking Vaccine

AbstractBackgroundVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced significant serum functional activity in both US and Malian adults. However, antibody titers declined rapidly, and transmission-reducing activity required four vaccine doses. Functional immunogenicity and durability must be improved before advancing TBV further in clinical development. We hypothesized that the pre-fertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.MethodsTransmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel®, and administered to mice, rhesus macaques, and humans. Antibody titers were measured by ELISA and transmission-reducing activity was assess by the Standard Membrane Feeding Assay.ResultsPfs25-EPA/Alhydrogel® and Pfs230D1-EPA/Alhydrogel® induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In U.S. adults, two vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel® recipients but no significant activity in five Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.ConclusionThe complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.Trial RegistrationClinicalTrials.govNCT02334462FundingThis work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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