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Safety, immunogenicity and efficacy of PfSPZ Vaccine against malaria in infants in western Kenya: a double-blind, randomized, placebo-controlled phase 2 trial

Abstract

The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-naïve adults. Preclinical studies show that T cell-mediated immunity is required for protection and is readily induced in humans after vaccination. However, previous malaria exposure can limit immune responses and vaccine efficacy (VE) in adults. We hypothesized that infants with less previous exposure to malaria would have improved immunity and protection. We conducted a multi-arm, randomized, double-blind, placebo-controlled trial in 336 infants aged 5–12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya (NCT02687373). Groups of 84 infants each received 4.5 × 105, 9.0 × 105 or 1.8 × 106 PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in the placebo group experienced related solicited adverse events (AEs) within 28 d postvaccination and most were mild. There was 1 grade 3-related solicited AE in the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more common in the highest-dose group (14.3%) compared to 6.0% of controls, with most being attributed to malaria. There was no significant protection against P. falciparum infection in any dose group at 6 months (VE in the 9.0 × 105 dose group = −6.5%, P = 0.598, the primary statistical end point of the study). VE against clinical malaria 3 months after the last dose in the highest-dose group was 45.8% (P = 0.027), an exploratory end point. There was a dose-dependent increase in antibody responses that correlated with VE at 6 months in the lowest- and highest-dose groups. T cell responses were undetectable across all dose groups. Detection of Vδ2+Vγ9+ T cells, which have been correlated with induction of PfSPZ Vaccine T cell immunity and protection in adults, were infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is age-dependent and may be influenced by Vδ2+Vγ9+ T cell frequency. Since there was no significant VE at 6 months in these infants, these vaccine regimens will likely not be pursued further in this age group.

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Fig. 1: Time to first/only parasitemia.
Fig. 2: PfSPZ Vaccine-induced adaptive immune response.
Fig. 3: PfSPZ Vaccine-induced γδ T cell response.
Fig. 4: PfSPZ Vaccine-induced humoral and B cell response.

Data availability

The data that support the findings of this study are available upon request to the corresponding authors and approval from Sanaria. Restrictions apply to the availability of these data, which were used under an investigational new drug application, so they are not publicly available. All requests for raw and analyzed data will be promptly reviewed by the trial sponsor, Sanaria, to verify if the request is subject to any confidentiality obligations. Patient-related data not included in the paper were generated as part of clinical trials and may be subject to patient confidentiality. Any data that can be shared will be released via a data use agreement.

Code availability

No custom code was generated for the analyses presented in this paper. Standard analysis packages and commands in the specified software were used.

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Acknowledgements

We thank the caregivers and infants and the study staff who made this study possible. We thank the data safety and monitoring board members for their careful review of safety data and recommendations: K. Kester (chair), A. Durbin, M. Molyneux, M. Spring, J. Ciolino and J. Otieno (local safety monitor). We thank the Sanaria Manufacturing and Quality Teams for providing the PfSPZ Vaccine for this study and W. Wijayalath for pharmaceutical operations support. We also thank the Sanaria Clinical and Regulatory team for supporting this trial. We thank the Kenya Medical Research Institute for support and for providing permission to publish the results. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention. This work was supported by the NIH Vaccine Research Center. Manufacturing and quality control release and stability assays for the PfSPZ Vaccine were supported in part by the National Institute of Allergy and Infectious Diseases, NIH (Small Business Innovation Research grant nos. 5R44AI055229-09A1 and 2R44AI058375-06A1 to S.L.H.).

Author information

Affiliations

Authors

Contributions

M.O., L.C.S., R.Y., S.L.H., T.L.R. and R.A.S. planned the study. M.O., R.Y., D.A., T.S., E.L.N., A.D., P.N.O., K.O., D.K.B., S.K., W.C. and A.M.S. conducted the study. B.K.L.S., E.R.J., N.K.C., P.F.B., T.L.R. and S.L.H. provided the study product. P.A.S.II, R.A.S., K.O., W.C. and N.K.C. conducted the laboratory and immunogenicity analyses. G.A. analyzed all the ECGs. R.E.W., D.S. and G.E.P. analyzed the data. S.J., S.A., C.D. and M.M. provided samples for the immunogenicity data. M.O., L.C.S., K.O., R.E.W., J.R.G., T.S., S.K., A.M.S., T.L.R., B.K.L.S., S.L.H., P.A.S.II and R.A.S. interpreted the study results. M.O., L.C.S., S.L.H., T.L.R., P.A.S.II and R.A.S. wrote the paper. All authors reviewed, edited and approved the paper.

Corresponding authors

Correspondence to Martina Oneko or Robert A. Seder.

Ethics declarations

Competing interests

T.L.R., N.K.C., P.F.B., E.R.J., B.K.L.S. and S.L.H. are employees of Sanaria, which manufactures the vaccine tested in this study. S.L.H. and B.K.L.S. are named inventors on patents related to the PfSPZ Vaccine. All other authors report no potential conflicts of interest.

Additional information

Peer review information Nature Medicine thanks Laurent Renia, W. Ripley Ballou, Kennedy Otwombe and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Alison Farrell was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Trial Profile.

Trial enrolment and participation details.

Extended Data Fig. 2 Proportional efficacy of PfSPZ Vaccine over time.

Proportional efficacy of various doses of PfSPZ Vaccine against Plasmodium falciparum parasitemia (>0 parasites/µL) at 3, 6, 9, and 12 months follow-up.

Extended Data Fig. 3 Survival analysis of first/only clinical malaria.

Kaplan-Meier survival analysis of time-to first or only clinical malaria episode over 12 months, by treatment group.

Extended Data Fig. 4 Flow cytometry gating for analysis of T cells.

(ag) Cellular gating tree using the 28-color panel outlined in Supplementry Information Tables 10 and 11. (a) Lineage gating of T cells. After gating on single cells, lymphocytes, and live CD3+ T cells, a pan-TCRγδ antibody was used to separate γδ and αβ T cells, which were further subdivided into CD4+ and CD8+ αβ T cells. (b) CCR7 and CD45RA antibodies were used to gate CD4+ and CD8+ αβ T cell naïve and memory subsets. Naive T cells (naïve), Central and transitional memory T cells (Tcm/Ttm), Effector memory T cells (Tem), and Effector T cells (Tef). (c) CD38 and HLA-DR were used to identify activated non-naïve CD4 and CD8 αβ T cells and γδ T cells. (d) CXCR5+ was used to identify blood T follicular helper (TfH) cells of non-naïve CD4 T cells, and blood TfH subsets were further characterized using PD-1 and CXCR3. (e) CD25 and CD127 were used to identify T regulatory cells (Tregs). (f) CD31 and CD45RA were used to identify recent thymic emigrants (RTEs) of CD4 T cells. (gi) Gating to measure T cell function following no stimulation or stimulation with PfSPZ. The panel used in Supplementary Table 10 was used for the functional gating of non-naïve CD4 and CD8 T cells in (g) and (h), respectively, while the panel in Supplementary Table 11 was used for the Th2 and Th17 gating of non-naïve CD4 T cells in (i). (j) TCR Vδ1 and Vδ2 antibodies were used to identify γδ T cell subsets. Vδ1 and Vδ1/Vδ2- T cell subsets were further analyzed for naïve (CD27+CD127+) vs clonal expansion (CX3CR1+CD127). Vγ9 was used to identify Vγ9+ or Vγ9- Vδ2+ T cells.

Extended Data Fig. 5 PfSPZ Vaccine-induced T cell responses.

(ad) T cell response to PfSPZ Vaccine. Percent of non-naïve CD4 T cells in the blood expressing IL-8 (A), IL-21 (b), Th2 cytokines (c), or IL-17 (d) at pre-immunization (blue) or 2 weeks after the 3rd immunization (red) of the indicated dose of PfSPZ Vaccine. Results are the percentage of cytokine-producing cells after incubation with PfSPZ minus the percentage of cytokine-producing cells after incubation with vaccine diluent (medium with 1% human serum albumin). Bars indicate median values within each group. Bars indicate median values and differences at each timepoint between pre and post vaccination groups were assessed using multiple T tests with Holm-Sidak’s correction for multiple comparisons. (e) A single PfSPZ-vaccinated adult PBMC sample was included in each batch as a positive control for PfSPZ stimulation. Each symbol represents the percent of non-naïve CD4 T cells expressing CD154, IFNγ, IL-2, or TNF (blue) or γδ T cells expressing IFNγ, IL-2, or TNF (red) in the positive control sample within a single batch. Green bars indicate median values. (f) Percent of non-naïve CD4 T cells expressing CD154, IFNγ, IL-2, or TNF or CD8 T cells expressing IFNγ, IL-2, or TNF in adult control samples following PMA/ionomycin stimulation.

Extended Data Fig. 6 Infection susceptibility correlates with pre-vaccination γδ T cell frequencies.

Pre-vaccination frequencies of Vδ1 (left) and Vδ2 (right) γδ T cell populations in subjects that were either uninfected (blue) or infected (red) during the vaccination period (dVax), during 3-month ATP, or during 6-month ATP. Differences at each timepoint between pre and post vaccination groups were assessed using multiple T tests with Holm-Sidak’s correction for multiple comparisons. *P<0.05, **P<0.01.

Extended Data Fig. 7 Net increase of IgG and IgM antibodies to PfCSP two weeks after the last dose of PfSPZ Vaccine in infants by dosage group who were followed for at least 3 months and 6 months.

Filled and unfilled circles represent uninfected (protected) and infected subjects.

Extended Data Fig. 8 Median and interquartile range of net OD 1.0 for IgG and IgM antibodies to PfCSP two weeks after the last dose of PfSPZ Vaccine in infants who were uninfected (protected) and infected during 3 months follow up.

Filled and unfilled circles represent uninfected (protected) and infected subjects.

Extended Data Fig. 9 Flow cytometry gating for phenotyping analysis of B/innate immune cells.

Cellular gating tree using the 25-color panel outlined in Supplementry Table 4. (A) Lineage gating includes gating on single cells, leukocytes, live cells, and then CD19 and CD3 are used to separate live B cells, T cells, and NK/myeloid cells. (B) T cell gating to identify γδ T cells (pan-γδ TCR) and mucosal-associated invariant T (MAIT) cells (CD161+TCRVα7.2+). (C) Gating for B cell populations. B cells were further divided into memory B cells (CD27+IgD+), immature B cells (CD10+CD21+), and atypical B cells (CD27-CD21+). Memory B cells were further divided into plasmablasts (CD38+CD20-), plasmodium (CSP)-specific B cells (CSP-probe+), and B cell isotypes using IgG and IgM antibodies. (D) Gating tree to identify various subsets of NK/myeloid cell populations. NK cell populations were first divided by CD56 expression. From the CD56- cell gate, monocyte subsets were characterized using CD14 and CD16. CD14-CD16- that were HLA-DR+ were used to identify dendritic cell (DC) populations including plasmacytoid DCs (pDCs) (CD123+CD11c-) myeloid-derived DCs (mDCs) (CD123-CD11c+). mDCs subsets were identified using CD1c and CD141.

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Oneko, M., Steinhardt, L.C., Yego, R. et al. Safety, immunogenicity and efficacy of PfSPZ Vaccine against malaria in infants in western Kenya: a double-blind, randomized, placebo-controlled phase 2 trial. Nat Med 27, 1636–1645 (2021). https://doi.org/10.1038/s41591-021-01470-y

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