Mosquirix (RTS,S)

A Novel Vaccine for the Prevention of Plasmodium falciparum Malaria

Kyle J Wilby BSP ACPR, PharmD; Tim TY Lau PharmD ACPR FCSHP; Samuel E Gilchrist MSc (Pharm), PhD; Mary HH Ensom PharmD FASHP FCCP FCSHP FCAHS

Disclosures

The Annals of Pharmacotherapy. 2012;46(3):384-393. 

In This Article

Therapeutic and Economic Issues and Controversies

RTS,S has demonstrated safety and efficacy for prevention of clinical disease associated with P. falciparum infection.[10–18] It has an efficacy rate ranging from 30% to 56%. Although efficacy rates nearing 100% would be ideal, complexity of the Plasmodium lifecycle and difficulty in vaccine design may justify these lower rates for a first-generation malaria vaccine. While RTS,S appears to be promising, a number of controversies need to be resolved before regulatory approval and distribution can be considered.

Duration of Immunity

A major question that needs to be addressed is longevity of protection. It is currently unknown how long the vaccine will provide immunity against development of clinical disease. Limited data from Phase 1 and 2 follow-up studies have suggested that clinical efficacy is maintained up to 12 months after the third dose of the RTS,S AS01E formulation,[17] and 45 months with AS02A.[16] Theoretically, the AS01E adjuvant should provide similar duration of protection, but there are no published reports beyond 12 months. Furthermore, it is known that anti-CS protein antibody titers decrease over time,[17] but it is unknown what titer level threshold is required for immunity to be present. An ongoing Phase 3 trial is currently assessing vaccine response at 32 months after the initial vaccine dose and will assist in addressing this question before product licensure.[14] Additionally, this study will evaluate efficacy of a booster dose given at 18 months and provide further insight into optimal vaccine usage.

Special Populations

Efficacy and safety of RTS,S require study in special populations that would likely benefit from immunization, including those with HIV, pregnancy, the malnourished, and travelers. Children with HIV or AIDS are especially vulnerable to morbidity associated with malaria infection, as they lack inherent immune responses. Although this subgroup would greatly benefit from an effective vaccine, it is unknown whether therapeutic antibody titers will be achieved with RTS,S, due to their immunocompromised status.[21]

Acquisition of malaria during pregnancy is associated with low birth weight, anemia, severe malaria, and death.[22] Rapid detection and treatment are considered standards of practice, but efficacy of therapy is reduced and incidence of adverse events is increased.[23] Thus, ability to prevent malarial disease would greatly benefit both the mother and the newborn. The studies so far with RTS,S have been only in healthy infants and children with the exclusion of those who are malnourished. Many children living in malaria-endemic regions do not have adequate nutrition, which may subsequently reduce their immunity and ability to fight infections. Malnutrition may further reduce the body's ability to elicit adequate immune response to the vaccine.

Lastly, travelers and expatriates may benefit from the immunity provided by a malaria vaccine while visiting endemic areas. However, further trials on its efficacy and safety are required before RTS,S is approved for widespread use in any of these special populations.

Cost-effectiveness

Cost burden of malarial disease requires comparison to the cost of immunization to determine cost-effectiveness of administering the RTS,S vaccine. Factors that require consideration include vaccine efficacy; effective duration of immunity; acquisition, distribution, and administrative costs of vaccine; potential cost savings on the health care system; patient-specific outcomes; and patient quality of life. As Phase 3 studies are completed, information regarding effects of the vaccine on malaria-related morbidity (anemia), hospitalization, and mortality will become available. Long-term follow-up from these studies is critical to characterize these clinical and economical outcomes to determine cost-effectiveness of the vaccine.

Future Considerations

Pending approval and licensing of the RTS,S vaccine, international authorities will need to work closely with the manufacturer and local governments to ensure that the product can be acquired and disseminated effectively to endemic areas. Collaborative efforts between national and international authorities are essential when determining utility of the vaccine. Resource-limited countries must be convinced of the vaccine's efficacy, safety, and cost-effectiveness on the health care system prior to investing in the product. International organizations (ie, WHO) will need to assess relative benefits of the vaccine to decide whether to provide endorsement, and work collaboratively with local governments and other international organizations to secure funding for access. Partnership programs between government and nongovernment organizations may have to be created to explore alternative funding strategies. If vaccine programs are initiated, careful monitoring of efficacy and safety outcomes will be essential for evaluation and justification of investments from governments and other stakeholders to ensure sustainability.[24]

Policies and procedures will be required to streamline the acquisition, storage, distribution, prescription, administration, and monitoring of the vaccine. To facilitate administration of the RTS,S vaccine, it could be added to the current WHO EPI vaccine program and coadministered with other recommended vaccinations on the immunization schedule, as no vaccine-vaccine interactions have been demonstrated.[11] However, further studies to confirm efficacy and safety of coadministration of the RTS,S vaccine with routine vaccines is required in the infant population. Although Phase 2 trials have suggested that this practice is effective, this will require confirmation in the ongoing Phase 3 trials.

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