Comments for:

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What is the real impact of the RTS,S malaria vaccine?

Submitter: Lode Schuerman | lode.schuerman@gsk.com

Authors: Lode Schuerman

GlaxoSmithKline

Published February 28, 2022

Dr. Zavala inaccurately referenced the efficacy of RTS,S/AS01 and how it compares to the R21/Matrix-M vaccine. Efficacy was reviewed by the European Medicine Agency and is summarized in the SmPC available at: https://www.ema.europa.eu/en/documents/outside-eu-product-information/mosquirix-product-information_en.pdf.

In addition, Dr. Zavala wrongly quoted the findings of the pilot implementation when stating that severe malaria was prevented in 30% of vaccinated children. This should read “RTS,S vaccination reduced severe malaria by 30%”. This reduction was observed in areas with widespread use of insecticide-treated bednets and good access to diagnosis and treatment. Furthermore, in seasonal malaria transmission settings, adding seasonal RTS,S vaccination to seasonal malaria chemoprevention (SMC) further reduced malaria incidence by 60–75% compared to SMC alone (Chandramohan D, et al. NEJM 2021;385:1005-17). This indicates that even stronger impact is possible when RTS,S is combined with other malaria interventions.

Vaccine efficacy (VE) against severe malaria remains unknown for the R21/MM vaccine, and the limited sample size in the ongoing phase II trial will likely not allow its estimation. In addition, VE can only be reliably assessed over the first 6 months of follow-up, as only few malaria cases occurred thereafter. These estimates were generated with two thirds of the children also receiving SMC (Datoo MS, et al. Lancet 2021;397:1809-18). In the same setting RTS,S showed 72% efficacy over the first 6 months of follow-up without any SMC coverage (RTS,S Clinical Trials Partnership. PLoS Med 2014;11:e1001685). Both R21 and RTS,S are based on the Plasmodium falciparum circumsporoite protein and use a saponin-based adjuvant. It is therefore reasonable to assume similar protection, although comparing the vaccines remains difficult considering the difference in SMC coverage and variability of VE estimates.

Any efficacious malaria program reduces the risk of infection, leading to delayed acquisition of natural immunity. The risk of rebound is therefore not limited to one particular intervention. Children in the phase II study referenced by Dr. Zavala only received 3 RTS,S doses. However, no rebound was seen with the 4-dose regimen in the phase III trial, and no rebound of severe malaria was noted over 7 years of follow-up (Tinto H, et al. Lancet ID 2019;19:821-32). RTS,S has an overall positive impact and provides protection throughout the age period when children are most vulnerable to malaria.

Conflict of interest statement:

LS is employee of, and has restricted shares in, the GSK group of companies.

 

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Response to Schuerman

Submitter: Fidel Zavala | fzavala1@jhu.edu

Authors: Fidel Zavala

Johns Hopkins Bloomberg School of Public Health

Published February 28, 2022

       The efficacy data of RTS,S described in my comment were obtained from the original peer reviewed publications  (ref. 6 and 7 of the Viewpoint) and represent the results obtained after three immunizations. Dr. Schuerman is correct to point out that a fourth dose administered 20 months after the first immunization increases - transitorily - the antibody response and efficacy.   I am also aware of recent trials that showed a reduction of  severe malaria when the administration of anti-malaria drugs is added to RTSS immunization. While these observations are intriguing, it is not evident that this is a sound long-term strategy to control malaria. The administration of these drugs may be beneficial in the short term; however, it may cause major long-term problems as malaria parasites have an extraordinary ability to develop drug resistance and this could have  serious consequences for the treatment of infections in the general population.  The appropriate assessment of a vaccine’s worth  should be based on the results of immunizations done in the absence of additional control measures and administered on a realistic vaccination schedule.   

     The efficacy of RTS,S was not “compared” with R21 as Dr. Schuerman suggests . R21 was mentioned as a “candidate on the horizon” and its efficacy is cited as it was reported in the original article (ref.10). I clearly stated that new trials were needed to compare R21 and RTS,S.

       As for the rebound of clinical malaria in children vaccinated with RTSS, these are complex occurrences that depend on the intensity of transmission and immunity to blood stages, and it is expected that the incidence of rebounds will differ amongst individuals and in different endemic areas. The malaria rebound described in Kenya (ref.18) might not be just an unusual event of a Phase II trial, as it was also described in the report cited by Dr. Schuerman  (Tinto H, et al. Lancet ID 2019;19:821-32) .  In this Phase III study, a rebound of clinical malaria was observed during the extension study period in one of the endemic sites (Nanoro). This increase in clinical malaria affected older children vaccinated with 3 or 4 RTS,S doses. The occurrence of malaria rebound in vaccinated children is a matter of importance and should not be dismissed. It merits the attention of those involved in vaccine design and implementation of new vaccination programs.

        There is no question that RTS,S represents an important achievement. However, it is also clear that a more efficient vaccine should be developed. Indeed, multiple academic centers, philanthropies and  governmental agencies are intensively working on the development of a new generation of malaria vaccines.