Environmental modifiers of RTS,S/AS01 malaria vaccine efficacy in Lilongwe, Malawi

Griffin J Bell, Matthew S Loop, Tisungane Mvalo, Jonathan J Juliano, Innocent Mofolo, Portia Kamthunzi, Gerald Tegha, Marc Lievens, Jeffrey Bailey, Michael Emch, Irving Hoffman, Griffin J Bell, Matthew S Loop, Tisungane Mvalo, Jonathan J Juliano, Innocent Mofolo, Portia Kamthunzi, Gerald Tegha, Marc Lievens, Jeffrey Bailey, Michael Emch, Irving Hoffman

Abstract

Background: RTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009-2014 phase III trial (MALARIA-055, NCT00866619), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted.

Methods: We implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6-12 weeks) and children (5-17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation.

Results: Vaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner.

Conclusions: Vegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called "dambos" which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context.

Trial registration: Efficacy of GSK Biologicals' Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009.

Keywords: Africa; Hansen Forest cover; Malaria; Malawi; RTS,S/AS01; Spatial analysis; Vaccine; Vaccine trial.

Conflict of interest statement

ML is a GSK employee and owns GSK shares in the GSK group of companies. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Forest/vegetation cover in Lilongwe City overlaid with OpenStreetMap rivers and participant household point locations This map was created in QGIS version 3.4.7 using Hansen forest cover data (available at:https://earthenginepartners.appspot.com/science-2013-global-forest/download_v1.6.html)
Fig. 2
Fig. 2
Household locations of participants in MALARIA-055 in Lilongwe District, plotted over traditional authority boundaries. This map was created in R version 3.5.1
Fig. 3
Fig. 3
Estimates of malaria prevalence in under-fives in Lilongwe city from 2011 to 2013 according to the MTI survey data. This map was created in R version 3.5.1
Fig. 4
Fig. 4
Probability of a participant having a grass roof (instead of a metal roof) throughout Lilongwe City This map was created in R version 3.5.1
Fig. 5
Fig. 5
Vaccine efficacy by roof type
Fig. 6
Fig. 6
Vaccine efficacy by vegetation cover (100 m buffer)

References

    1. World Health Organization, Global Malaria Programme. World malaria report 2019. 2019.
    1. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. The Lancet. 2015;386(9988):31–45.
    1. Olotu A, Fegan G, Wambua J, Nyangweso G, Leach A, Lievens M, et al. Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children. N Engl J Med. 2016;374(26):2519–29.
    1. Tinto H, Otieno W, Gesase S, Sorgho H, Otieno L, Liheluka E, et al. Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial. Lancet Infect Dis. 2019;19(8):821–832. doi: 10.1016/S1473-3099(19)30300-7.
    1. Moorthy VS, Hutubessy R, Newman RD, Hombach J. Decision-making on malaria vaccine introduction: the role of cost-effectiveness analyses. Bull World Health Organ. 2012;90(11):864–866. doi: 10.2471/BLT.12.107482.
    1. Drakeley C, Abdulla S, Agnandji ST, et al. Longitudinal estimation of plasmodium falciparum prevalence in relation to malaria prevention measures in six sub-Saharan African countries. Malar J. 2017;16:433. doi: 10.1186/s12936-017-2078-3.
    1. Wood SN. Royal Statistical Society Publications [Internet]. [cited 2018 Dec 25]. Available from: .
    1. Tusting LS, Ippolito MM, Willey BA, Kleinschmidt I, Dorsey G, Gosling RD, et al. The evidence for improving housing to reduce malaria: a systematic review and meta-analysis. Malar J. 2015;14:209.
    1. Rutsein SO, Johnson K. The DHS wealth index. DHS comparative reports no. 6. Calverton, Maryland, USA: ORC Macro. 2004.
    1. Janko MM, Irish SR, Reich BJ, Peterson M, Doctor SM, Mwandagalirwa MK, et al. The links between agriculture, Anopheles mosquitoes, and malaria risk in children younger than 5 years in the Democratic Republic of the Congo: a population-based, cross-sectional, spatial study. Lancet Planet Health. 2018;2(2):e74–82.
    1. Mloza-Banda HR, Banda JW, Lunduka R, Mohamoud MY. The Dambo ecosystem of the Diamphwe and Lilongwe River catchments in Central Malawi. I. Appraisal of resources availability and use. UNISWA research journal of agriculture, science and Technology. 2001;5.
    1. Hansen MC, Potapov PV, Moore R, et al. Townshend. 2013. “High-Resolution Global Maps of 21st-Century Forest Cover Change.” Science 342 (15 November): 850–53. Data available on-line from: .
    1. OpenStreetMap contributors. 2015. Planet dump [Data file from 09/19/2018]. Retrieved from ..
    1. R Core Team. R: a language and environment for statistical computing. R Foundation for statistical computing, Vienna, Austria. 2017. URL .
    1. Bates D, Maechler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Software. 2015;67(1):1–48. doi: 10.18637/jss.v067.i01.
    1. Dicko A, Greenwood B. Malaria vaccination and rebound malaria. Lancet Infect Dis. 2019;19(8):790–791. doi: 10.1016/S1473-3099(19)30282-8.
    1. Bell GJ, Loop M, Topazian HM, Hudgens M, Mvalo T, Juliano JJ, et al. Case reduction and cost-effectiveness of the RTS,S/AS01 malaria vaccine alongside bed nets in Lilongwe, Malawi. Vaccine. 2020;38(25):4079–87.
    1. Han L, Hudgens MG, Emch ME, Juliano JJ, Keeler C, Martinson F, et al. RTS,S/AS01 Malaria Vaccine Efficacy is Not Modified by Seasonal Precipitation: Results from a Phase 3 Randomized Controlled Trial in Malawi. Sci Rep. 2017;7(1):7200.

Source: PubMed

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