Remarks

• The RTS,S/AS01 malaria vaccine should be provided in a four-dose schedule in children from 5 months of age.
• Countries may consider providing the RTS,S/AS01 vaccine seasonally, with a five-dose strategy, in areas with highly seasonal malaria or with perennial malaria transmission with seasonal peaks.
• Countries that choose to introduce the vaccine in a five-dose seasonal strategy are encouraged to document their experiences, including adverse events following immunization.
• RTS,S/AS01 malaria vaccine should be provided as part of a comprehensive malaria control strategy.

Practical Info Vaccine characteristics, content, dosage, administration and storage RTS,S/AS01 is a pre-erythrocytic recombinant protein vaccine, based on the RTS,S recombinant antigen. It comprises the hybrid polypeptide RTS, in which regions of the P. falciparum circumsporozoite protein known to induce humoral (R region) and cellular (T region) immune responses are covalently bound to the hepatitis B virus surface antigen (S). The vaccine is currently produced as a two-dose RTS,S powder to be reconstituted with a two-dose AS01 adjuvant system suspension. After reconstitution, the total volume is 1ml (two doses of 0.5 ml). No preservative is included in either the RTS,S formulation or the AS01 adjuvant system. The vials should therefore be discarded at the end of the vaccination session, or within six hours after opening, whichever comes first. The reconstituted 0.5ml vaccine should be administered by injection into the deltoid muscle in children aged 5 months or older. The shelf life of the RTS,S/AS01 vaccine is three years. A vaccine vial monitor is on the AS01 vial [140]. Schedule WHO recommends that the first dose of vaccine be administered from 5 months of age. There should be a minimum interval of four weeks between doses. The vaccine should be administered in a three-dose primary schedule, with a fourth dose provided 12–18 months after the third dose to prolong the duration of protection. However, there can be flexibility in the schedule to optimize delivery, for example, to align the fourth dose with other vaccines given in the second year of life. Children who begin their vaccination series should complete the four-dose schedule [149]. Optional schedule for settings with highly seasonal malaria or perennial malaria with seasonal peaks Countries may consider providing the RTS,S/AS01 vaccine seasonally, with a five-dose strategy in areas with highly seasonal malaria or with perennial malaria transmission with seasonal peaks. This strategy seeks to maximize vaccine impact by ensuring that the period of highest vaccine efficacy (just after vaccination) coincides with the period of highest malaria transmission. The primary series of three doses should be provided at monthly intervals, with additional doses provided annually prior to the peak transmission season. Countries that choose seasonal deployment of the RTS,S/AS01 vaccine are strongly encouraged to document their experiences, including the vaccine’s effectiveness, feasibility and occurrence of any adverse events following immunization—as additional input for future updates to the guidance. WHO also encourages international and national funders to support relevant learning opportunities [149]. Co-administration RTS,S/AS01 given in conjunction with routine childhood vaccines has been evaluated in several trials [154][155]. Non-inferiority criteria were met for all vaccines given with RTS,S/AS01, in comparison with 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 [140]. No co-administration studies have been conducted with RTS,S/AS01 and meningococcus A, typhoid conjugate, cholera, Japanese encephalitis, Tick-borne encephalitis, rabies, mumps, influenza or varicella vaccines [149]. Identifying areas for vaccine introduction Decisions about where to introduce the malaria vaccine should be made in the context of national planning of mixes of malaria interventions and strategies and considering the need for subnational tailoring of packages of interventions. Subnational tailoring considers variations in malaria epidemiology, health system structure and function, and broader contextual considerations. Current WHO guidance defines moderate or high transmission settings as those with an annual incidence greater than about 250 cases per 1000 population or a prevalence of P. falciparum infection in children aged 2—10 years (PfPR2-10) of approximately 10% or more. These are indicative values and should not be used as strict thresholds. Vaccine safety The RTS,S/AS01 vaccine is safe and well tolerated. There is a small risk of febrile seizures within seven days (mainly within 2—3 days) of vaccination. As with any vaccine introduction, proper planning and training of staff to conduct appropriate pharmacovigilance should take place beforehand. The only contraindication to use of RTS,S/AS01 vaccine is severe hypersensitivity to any of the vaccine components [140]. Vaccination of special populations Malnourished or HIV-positive infants may be vaccinated with the RTS,S/AS01 vaccine using a standard schedule. These children may be at particular risk from malaria infection and the vaccine has been shown to be safe in these groups. The vaccine should be provided to infants and young children aged 5—17 months of age who relocate to an area of moderate to high transmission, including during emergency situations. The vaccine has been developed for use in young children living in malaria-endemic settings, and has not undergone full clinical testing in adults, nor is it recommended for adults. The vaccine is not indicated for travellers, who should use chemoprophylaxis and vector control methods to prevent malaria when traveling to endemic settings. Surveillance As for all new vaccines, the effectiveness and safety of the RTS,S/AS01 vaccine should be monitored post-introduction. Countries that choose to introduce the vaccine in a five-dose seasonal strategy are encouraged to document their experience, including adverse events following immunization. Research priorities The WHO-coordinated Malaria Vaccine Implementation Programme will continue through 2023, with continued monitoring of data on safety, impact, coverage achieved and the added benefit of the fourth dose. In areas with highly seasonal malaria or with perennial malaria transmission with seasonal peaks, operational research is needed specifically related to the seasonal delivery of vaccine doses, including annual preseason dosing after a primary series given through the routine health clinics. Further evaluation will be required to determine how best to deliver the combination of SMC and seasonal malaria vaccination in areas. Data should be collected on safety, immunogenicity, and effectiveness of annual doses beyond the fifth dose. Considerations for immunization and health systems The additional visits needed for RTS,S/AS01 are opportunities to provide other integrated 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 and other preventive interventions, and remind parents of the importance of continuing to use an ITN every night and seeking prompt diagnosis and treatment for fever. A framework for allocation of limited supply Supplies of the RTS,S/AS01 vaccine are expected to be limited in the short to medium term, and demand is expected to be high. WHO is working with partners to develop a framework to guide the allocation of the initial limited doses of malaria vaccine, using a transparent process that incorporates input from key parties, with appropriate representation and consultation. This framework will include dimensions of market dynamics, learning from experience, scientific evidence for high impact, implementation considerations and social values, including fairness and equity.