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Existing malaria intervention strategies require an additional tool to control and eliminate malaria.
The promising safety and efficacy of the R21 vaccine make it an effective intervention strategy for malaria elimination.
Prevalence of both P. falciparum and P. vivax in children under five, in different malaria transmission settings in India needs to be considered.
A vaccine that targets both P. falciparum and P. vivax in all age groups and inhibits transmission will be more suitable for India’s malaria elimination goal.
An effective and sustainable vaccine as a complementary intervention strategy may require operational research evidence.
Introduction
Malaria, a longstanding and life-threatening disease, contributes to approximately 249 million global cases.1 Plasmodium falciparum, among the five Plasmodium species, stands out as the most fatal, responsible for more than 95% of malaria morbidity and mortality worldwide.1 Given the substantial threat posed by malaria, the development of a vaccine targeting P. falciparum becomes a global imperative to mitigate its adverse effects.
In 2023, India reported approximately 227564 cases of malaria, with 60% of these attributed to the P. falciparum, which led to 83 deaths.2 While India has made strides in managing malaria through interventions like indoor residual spraying, long-lasting insecticidal nets and early diagnosis and complete treatment, achieving an optimal vaccine becomes pivotal in the country’s quest for malaria elimination. Notably, India witnessed the largest relative decrease in malaria cases in 2022 compared with the previous year.1 The article delves into the significance of two WHO-approved malaria vaccines—RTS,S/AS01 and R21/Matrix-M, endorsed in 2021 and 2023, respectively.3 4 It provides a comprehensive discussion on the potential perspectives and implications of these vaccines for India’s ongoing efforts for malaria elimination.
Indian malaria elimination target
India has committed to achieve the elimination of malaria by the year 2030 in alignment with the WHO’s Global Technical Strategy for malaria spanning from 2016 to 2030. India launched its first malaria elimination document, ‘National Framework for Malaria Elimination (NFME) (2016–2030)’ in 2016.5 The goal was to eliminate malaria from the 26 states/union territories characterised by low (Category 1) and moderate (Category 2) transmission by 2022. Additionally, the aim was to decrease the malaria incidence to below 1 case per 1000 population annually in all states, union territories and their respective districts by 2024. Since the launch of the NFME, India has achieved a reduction of about 85% and 78% in the number of malaria morbidity and mortality respectively. Districts were considered as units of planning and implementation for malaria elimination. Early diagnosis and treatment and vector control through different strategies are the main interventions suggested in the NFME.5 The goal of malaria elimination faces significant challenges due to the growing antimalarial and insecticide resistance, as well as the existence of asymptomatic and submicroscopic malaria.6
RTS,S/AS01
RTS,S vaccine was the first malaria vaccine approved by WHO.7 This vaccine is particularly suitable for regions with moderate-to-high P. falciparum malaria transmission like sub-Saharan Africa.7 The RTS,S/AS01 vaccine is a pre-erythrocytic vaccine and targets the circumsporozoite protein (CSP) antigen.7 AS01 was determined to be the most effective adjuvant that increases anti-CSP antibody and CD4+T-cell responses.7
The RTS,S/AS01 vaccine induces cell-mediated immunity that activates its T cells, which help to destroy the sporozoites that have invaded the liver cells. Four doses are administered intramuscularly for RTS,S/AS01, first dose at the age of 5 months and interval between doses must be 1 month. Completion of the primary series of dosage is by 9 months of age. A booster dose is recommended after 1 year of administration of the fourth dose in malaria-endemic areas.7 8 The vaccine efficacy was 34% against severe malaria in a phase 3 randomised control trial carried out at 11 African sites.8
R21/Matrix-M
The R21/Matrix-M vaccine is a subunit vaccine intended to prevent paediatric malaria that also targets CSP. It is the first vaccine to achieve the WHO-specified goal of 75% efficacy.4 It received regulatory clearance for use in Ghana on 13 April 2023. It was recommended for use by the WHO on 2 October 2023.4 It has been demonstrated to dramatically lower the incidence of malaria cases and fatalities in children. It has high efficacy when given just before the high transmission season.
The RTS,S/AS01 vaccine, and the R21 malaria vaccine work in a similar fashion. However, an adjuvant based on saponins, Matrix-M, is used in R21 to boost the vaccine’s humoral and cellular immune responses.9 Once the CSP antigen molecules have adsorbed to the Matrix-M particles, it is taken up by dendritic cells. The dendritic cells are activated by the Matrix-M adjuvant in the R21 vaccine. The dendritic cells transport the CSP antigen to lymph nodes and the CSP antigen is presented to B and T lymphocytes. The B cells develop into plasma cells and generate CSP-specific antibodies while the T cells develop into helper T cells and cytotoxic T cells.9
Similar to RTS,S/AS01, the R21/Matrix-M vaccine must be given in four doses intramuscularly: starting from the age of 5 months. In addition, an additional booster dosage is now being investigated and could be advised for children who require extra protection, such as those living in areas where there is a significant malaria risk remain, one year after receiving the fourth dose.4
Usefulness of R21/Matrix-M vaccine
Although there is no evidence to date to show which of the two WHO-recommended vaccines performs better than the other. However, the literature on both vaccines shows that there is a 77% decrease in clinical incidences of malaria in children 5–17 months of age with the R21/Matrix-M vaccine. It reduces the risk of severe malaria by 75% as compared with 30–40% for RTS,S/AS01. Furthermore, particularly in young infants, R21/Matrix-M seems to have a more favourable safety profile in comparison to RTS,S/AS01 in which fewer adverse events and significant side effects have been observed.9 Since R21/Matrix-M generates both cell-mediated and humoral immune response, hence, a higher immune response against the CSP protein as compared with RTS,S/AS01. This might add to its increased effectiveness and offer protection that might last longer.10
Context and challenges of RTS,S/AS01 and R21/MatrixM for India
Vaccine trials have been conducted in the WHO African region, and the vaccine has been implemented solely in countries within that region as part of the malaria control programme.11 The big factor favouring the vaccine implementation in the region is the high prevalence of P. falciparum. The significance of malaria vaccines in India becomes apparent when considering the prevailing malaria morbidity and mortality trends. However, the disease dynamics in India are different from that of the WHO African region. Both P. falciparum and P. vivax are prevalent in India, about 35% of cases are due to P. vivax.2 Children under 5 years of age are the major contributor to malaria in the African region and contribute to about 80% of malaria deaths in the region. In areas with a high prevalence of paediatric malaria, achieving good vaccine coverage may significantly reduce malaria transmission within the community. It may lead to herd immunity, indirectly benefiting the entire community. The randomised control trial of R21/Matrix-M in Burkina Faso also showed very promising results. The percentage of malaria cases in children under 5 years of age in Burkina Faso was about 40% in 2021.12 The existing studies emphasise the substantial impact of malaria on different age groups.6 Notably, the percentage of cases in India under 5 age group varies from 5–20%.13–16 The mortality was found to be highest in the age group >4–5 years in one of the endemic areas in India.17 Notably, the WHO endorsed the pilot implementation of the RTS,S/AS01 vaccine in 2021, particularly in regions with moderate-to-high malaria transmission (Annual Parasite Index >250). However, India comes under a very low transmission setting, API 0.18 for the year 2023.2 Taking into account the low API, the vaccine’s limited efficacy, species-specific targeting and inability to prevent transmission, RTS,S/AS01 may not be the optimal choice.3
The R21 vaccine has demonstrated efficacy, reducing symptomatic cases by 75% over 12 months following a three-dose series, particularly in season transmission settings when administered before peak transmission seasons.18 In India, where seasonal malaria transmission is a significant concern, the timing and intensity of outbreaks are influenced by monsoon seasons.2 The R21/Matrix-M malaria vaccine may present a promising avenue for reducing the malaria burden in India, especially in historically endemic regions. However, despite the WHO approval, this vaccine is still less effective compared with standard childhood vaccines such as Polio (90–99% efficacy).19 It targets only P. falciparum and the efficacy established is for clinical malaria cases only. In India, approximately 80% of malaria cases and major transmission reservoir is in the age groups that are not currently targeted by existing malaria vaccines.20 Both prevalent Plasmodium species, P. falciparum and P. vivax, have been reported to cause severe malaria in these age groups.21 Addressing this gap is crucial for comprehensive malaria control and prevention, to ensure that the majority of those at risk are protected.
The applicability of R21 needs to be established in India as trials for it have not been conducted in India. The trials in India are more challenging due to the low malaria prevalence in children under 5 years of age and the significant contribution by P. vivax infections. However, the R21 vaccine can be used in research mode in the specified pockets of high malaria in the country. The vaccine characteristics that may help in achieving the goal of malaria elimination are shown in figure 1.
Malaria vaccine for a malaria-free world: Future vaccines that can give coverage to all age groups, dominant Plasmodium species, have efficacy like other standard childhood vaccines and provide protection against infection/transmission will accelerate the journey for a malaria-free world. The text in green blocks signifies the features of the current malaria vaccines. The text in orange are features that will increase the applicability of the of malaria vaccine in different epidemiological settings.
Conclusion
The introduction of malaria vaccines, such as R21/Matrix-M, has sparked renewed optimism in the global fight against malaria. The encouraging effectiveness and safety of the R21 vaccine provide an argument for its use in India’s mission of malaria elimination. The R21/Matrix-M vaccine could have emerged as a key ally, but the unknown/low P. falciparum prevalence in children under 5 years of age, very low malaria transmission and P. vivax malaria are the important factors to be considered. Considering low malaria mortality in India, a vaccine that may target both P. falciparum and P. vivax in all age groups and prevent transmission will be more fruitful for the malaria elimination goal. The imperative of including vaccines to augment the effectiveness of existing strategies demands substantiation through research-based evidence.
Data availability statement
The data used in the manuscript are from open access sources and are available in the public domain.
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Footnotes
Handling editor Fi Godlee
X @DrRanjha107
Contributors RR and PKB conceived the idea. RR, PB, MM and KS wrote the manuscript. PKB and ARA edited the manuscript. RR is the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.