Remarks

• Countries should prioritize vaccination in areas of moderate and high transmission [i]. However, countries may also consider providing the vaccine in low transmission settings. Decisions on expanding malaria vaccination to low transmission settings should be considered at country level on the basis of the overall malaria control strategy, affordability, cost-effectiveness and programmatic considerations, such as whether the inclusion would simplify delivery.
• Malaria vaccines should be provided in a four-dose schedule in children from 5 months of age for the reduction of malaria disease and burden [ii]. Countries may choose to give the first vaccine dose earlier than 5 months of age on the basis of operational considerations to increase coverage or impact.
• The minimum interval between any doses is four weeks; however, to achieve prolonged protection, the fourth dose should be given 6–18 months after the third dose.
• To improve coverage, there can be flexibility in the timing of the fourth dose, including by aligning it with vaccines given in the second year of life. Alternatively, because the vaccine efficacy is highest in the first months after vaccination, the fourth dose can be given just prior to seasonal peaks in malaria transmission to optimize vaccine efficacy.
• A fifth dose, given one year after the fourth dose, may be provided in areas of highly seasonal transmission and may be considered in other areas where a significant malaria risk remains for children, depending on a local assessment of feasibility and cost-effectiveness.
• In areas with highly seasonal malaria transmission or perennial malaria transmission with seasonal peaks, countries may consider providing the vaccine using an age-based or seasonal approach. Alternatively, countries could consider a hybrid of these approaches, giving the first three doses through age-based administration and subsequent annual doses seasonally [iii].
• At the time of vaccine introduction, catch-up vaccination can be considered in children up to 5 years of age, subject to local epidemiology and age of high risk, feasibility, affordability and vaccine availability.
• Malaria vaccines should be provided as part of a comprehensive malaria control strategy. All malaria control interventions, including vaccines, provide partial protection; the highest impact is achieved when a mix of interventions is used. Appropriate mixes of interventions (ITNs, preventive chemotherapies, vaccines, etc.) should be identified for different subnational settings. These mixes are defined by national malaria programmes on the basis of the local malaria epidemiology (e.g. intensity of transmission, age pattern of severe disease, vector species and behaviour, and insecticide and drug resistance patterns) and contextual factors (e.g. structure and function of the health care system). [i] Moderate and high transmission settings are defined as areas with a P. falciparum parasite prevalence greater than 10% PfPR2-10 or an annual parasite incidence greater than 250 cases per 1000 population. These thresholds are indicative and should not be regarded as absolutes for determining the applicability of the malaria vaccine recommendation. [ii] Although the WHO prequalification issued for the RTS,S/AS01 and R21/Matrix-M malaria vaccines permits children to receive the first dose from 5 months of age, the RTS,S/AS01 manufacturer’s licensure specifies from 6 weeks to 17 months of age. Studies with RTS,S/AS01 indicated lower efficacy if the first dose was given around 6 weeks of age. However, the efficacy of RTS,S/AS01 and R21/Matrix-M vaccines is unlikely to be reduced substantially if the first dose is given at 4, rather than 5, months of age. [iii] An age-based vaccination approach provides the first three vaccine doses when children become age-eligible (with a minimum of four weeks between doses) and a fourth dose 6–18 months after the third dose. A seasonal vaccination approach provides the first three vaccine doses just prior to the malaria transmission season (with a minimum of four weeks between doses) and subsequent doses just prior to the transmission season. A hybrid vaccination approach involves giving the first three doses through an age-based approach and subsequent doses just prior to the transmission season.

Practical info Vaccine characteristics, content, dosage, administration and storage RTS,S/AS01 and R21/Matrix-M are pre-erythrocytic vaccines targeting the central repeat amino acid sequence Asn-Ala-Asn-Pro (NANP) region of the P. falciparum circumsporozoite protein (CSP). Both vaccines are recombinant protein virus-like particles formed from a fusion protein comprising the CSP region and hepatitis B virus surface antigen (hBsAg) nanoparticles. This recombinant fusion protein is produced through expression in yeast (Saccharomyces cerevisiae for RTS,S and Hansenula polymorpha for R21). The formulation of RTS,S/AS01 consists of 25 μg of RTS,S with the AS01 adjuvant system. This adjuvant system contains the immunomodulatory molecules 3-O-desacyl-f4-monophosphoryl lipid A and a saponin derived from the bark of the Quillaja saponaria tree (QS21) together with liposomes. The RTS,S antigen is lyophilized and needs to be reconstituted with the liquid AS01 adjuvant suspension prior to administration. The vaccine is produced as a two-dose RTS,S powder to be reconstituted with a two-dose AS01 adjuvant suspension. After reconstitution, the total volume is 1 mL (two doses of 0.5 mL each).[186] 21/Matrix-M consists of 5 µg of R21 and 50 µg of Matrix-M, a saponin-derived adjuvant, and is available as a fully liquid singlevial formulation. Each R21/Matrix-M dose is 0.5 mL, with one-dose and two-dose vials available.[187] Neither of the vaccines includes a preservative, and vials should therefore be discarded at the end of the vaccination session or within six hours of opening, whichever comes first. The vaccines should be stored at 2–8°C. The shelf-life is three years for RTS,S/ AS01 and two years for R21/Matrix-M. A vaccine vial monitor (VVM Type 14) is on the RTS,S/AS01 reconstitution vial and the R21/Matrix-M vial cap.[186][187] Schedule Malaria vaccines should be provided in a four-dose schedule in children from 5 months of age for the reduction of malaria disease and burden. Countries may choose to give the first vaccine dose earlier than 5 months of age on the basis of operational considerations, to increase coverage or impact.[iv] The minimum interval between any doses is four weeks; however, to achieve prolonged protection, the fourth dose should be given 6–18 months after the third dose. To improve coverage, there can be flexibility in the timing of the fourth dose, including by aligning it with vaccines given in the second year of life. Alternatively, because vaccine efficacy is highest in the first months after vaccination, the fourth dose can be given just prior to seasonal peaks in malaria transmission to optimize vaccine efficacy. A fifth dose, given one year after the fourth dose, may be provided in areas of highly seasonal transmission and, depending on a local assessment of feasibility and cost-effectiveness, may be considered in other areas where a significant malaria risk remains for children. In areas with highly seasonal malaria transmission or perennial malaria transmission with seasonal peaks, countries may consider providing the vaccine using an age-based or seasonal approach. Alternatively, countries could consider a hybrid of these approaches, giving the first three doses through age-based administration and subsequent annual doses seasonally. At the time of vaccine introduction, catch-up vaccination can be considered in children up to 5 years of age, subject to local epidemiology and age of high risk, feasibility, affordability and vaccine availability. [iv] Although the WHO prequalification issued for the RTS,S/AS01 and R21/Matrix-M malaria vaccines permits children to receive the first dose from 5 months of age, the RTS,S/AS01 manufacturer’s licensure specifies from 6 weeks to 17 months of age. Studies with RTS,S/AS01 indicated lower efficacy if the first dose was given around 6 weeks of age. However, the efficacy of RTS,S/AS01 and R21/Matrix-M vaccines is unlikely to be reduced substantially if the first dose is given at 4, rather than 5, months of age. Alternative schedules, fractional or reduced-dose schedules To date, efficacy has been demonstrated for a total of seven seasonally targeted doses of RTS,S/AS01 over five high transmission seasons, given as three monthly doses followed by annual doses just prior to the subsequent four high transmission seasons [191]. Efficacy has also been demonstrated for four seasonally targeted doses of R21/Matrix-M over two high transmission seasons [182]. A clinical trial explored alternative vaccine schedules for RTS,S/AS01, including the use of a fractional third and fourth dose to increase vaccine efficacy or for dose-sparing [192][193]. The trial did not show superiority of fractional-dose schedules over the full-dose schedules, although all regimens demonstrated statistically significant vaccine efficacy against clinical malaria compared to the comparator arm (rabies vaccine). The value of the fourth dose is being further evaluated with RTS,S/AS01 as part of the pilot evaluations in Ghana, Kenya and Malawi and in an ongoing case-control study (NCT05041556) [194]. Product choice The choice of product to be used in a country should be based on the product characteristics and programmatic considerations, as well as vaccine supply and long-term affordability. Interchangeability The malaria vaccination series for each child should be completed with the same product whenever feasible. However, if the product used for a prior dose is unavailable or unknown, the series should be completed with either of the available WHO-recommended malaria vaccines. Restarting the vaccine series is not recommended. Co-administration RTS,S/AS01 given in conjunction with routine childhood vaccines has been evaluated in several trials [195][196]. Non-inferiority criteria were met for all vaccines given with RTS,S/AS01, compared to the same vaccines given without RTS,S/AS01. RTS,S/ AS01 can be given concomitantly with any of the following monovalent or combination vaccines: diphtheria, tetanus, whole-cell pertussis, acellular pertussis, hepatitis B, Haemophilus influenzae type b, oral poliovirus, measles, rubella, yellow fever, rotavirus and pneumococcal conjugate vaccines [178]. A study is currently under way to assess the safety and immunogenicity of R21/ Matrix-M co-administered with yellow fever and measles-rubella vaccine and pentavalent (diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type b), rotavirus, pneumococcal and oral poliovirus vaccines (NCT05155579) [197]. Role of the malaria vaccine among other preventive measures Malaria vaccines should be provided as part of a comprehensive malaria control strategy. All malaria control interventions, including vaccines, provide partial protection; the highest impact is achieved when a mix of interventions is used. Appropriate mixes of interventions (ITNs, preventive chemotherapies, vaccines, etc.) should be identified for different subnational settings. These mixes are defined by national malaria programmes on the basis of the local malaria epidemiology (e.g. intensity of transmission, age pattern of severe disease, vector species and behaviour, and insecticide and drug resistance patterns) and contextual factors (e.g. structure and function of the health care system). The additional visits needed to administer the malaria vaccine are opportunities to provide other integrated malaria control and preventive health services. Efforts should be made to take advantage of these visits to catch up on missed vaccinations, administer vitamin A, carry out deworming, provide ITNs and other preventive interventions, and remind parents and/or caregivers of the importance of continuing to use an ITN every night, using other malaria preventive measures as recommended, and seeking prompt diagnosis and treatment for fever. Vaccine safety Both RTS,S/AS01 and R21/Matrix-M vaccines are considered to be safe and well tolerated. There is a small risk of febrile seizures within seven days (mainly within 2–3 days) of vaccination [186][187]. As with any vaccine introduction, proper planning and training of staff to conduct appropriate pharmacovigilance should take place beforehand. Malaria vaccines should not be given to anyone who has experienced a severe allergic reaction after a previous hepatitis B vaccination or malaria vaccine dose or to a vaccine component [186][187]. Vaccination of special populations Malnourished children may be at particular risk of malaria infection and can be vaccinated with either vaccine. RTS,S/AS01 can be given to children with HIV infection. RTS,S/AS01 has been evaluated in infants with a history of preterm birth (before 37 weeks’ gestation) and/or low birth weight, in HIV-exposed or in HIV-infected infants and children, and in malnourished infants and children. The vaccine was found to be well tolerated and immunogenic in all groups. Antibody titres were lower in HIV-infected children than in children with an unknown or negative HIV status. A study is currently under way to assess the safety and immunogenicity of R21/Matrix-M in HIV-positive (WHO HIV stage 1 or 2 disease) children aged 5–36 months (NCT05385510) [198]. The trial of R21/Matrix-M in HIV-positive infants is ongoing and data are not yet available; therefore, there remains a possibility that the efficacy of R21/Matrix-M could be impaired in these children. The malaria vaccine should be provided to infants and young children who relocate to an area of moderate or high transmission, including during emergency situations. Countries are encouraged to consider strategies to improve coverage in populations with high need and at high risk of malaria burden and disease, including under-vaccinated children, hard-to-reach or marginalized populations, persons in areas of conflict or emergency situations, displaced populations, or those in other areas with poor access to health services. Some of these populations may benefit from delivery through campaigns. The vaccines are not recommended for use in adults (including health workers and pregnant persons). The vaccine is not indicated for travellers, who should use chemoprophylaxis and vector control methods to prevent malaria when travelling to endemic settings. Surveillance As for other vaccines, surveillance should be in place to monitor malaria vaccine safety. The prompt and rigorous investigation of any potentially linked SAEs also serves to maintain confidence in the immunization programme. Research priorities For all WHO-recommended malaria vaccines, operational research is needed, specifically in relation to the seasonal delivery approach. The research should include annual pre-transmission season dosing after three doses given through age-based delivery, and how best to deliver the combination of SMC and seasonal malaria vaccination. Countries are encouraged to document and evaluate their experience with malaria vaccine introductions – in particular for seasonal deployment of the vaccine, expanded age range, or a five-dose schedule – to provide additional input for future updates to the guidance, including on vaccine effectiveness, feasibility and the occurrence of adverse events following immunization. Monitoring and evaluation of immunogenicity and reactogenicity of mixed vaccine use is not required but should be documented where feasible. A number of research priorities have been identified for R21/Matrix-M. However, introduction should not be delayed pending the completion of these studies. These priority research topics include: co-administration with childhood vaccines; post-licensure studies on vaccine effectiveness in high perennial transmission settings; impact on severe malaria and mortality; monitoring of safety in infants and young children; and interchangeability studies to evaluate safety and effectiveness in children who receive different malaria vaccines in the same schedule. WHO also encourages international and national funders to support relevant learning opportunities.