Respiratory Syncytial Virus (RSV) is a virus that affects the respiratory system and easily spreads from one person to another. The virus is a leading cause of hospitalization for infections that affect the lower part of the respiratory tract (LRTIs) among young children aged 0-59 months globally, contributing 30%-80% of all hospitalizations. In Kenya, respiratory disease surveillance systems indicate substantial impact of disease due to RSV infection in children under 5 years of age, particularly among young children under one year, and substantial excess deaths associated with RSV emphasizing impact on children under 5 years and adults over 50 years of age. Vaccination remains the only strategy for preventing severe RSV disease among high-risk populations. A new RSV vaccine (RSVA/B-preF vaccine with the brand name, Abrysvo™) has been shown to be safe for both mother and baby, and protective against severe forms of respiratory illness associated with RSV. This vaccine is now licensed for use in pregnant women in a number of high-income countries, and its licensure is underway in other African countries. It has also been licensed for pregnant women from 28 to 36 weeks of GA in South Africa and 24 to 36 weeks of GA in Ghana, The Gambia and Kenya. Nevertheless, the main study/trial (phase III study of RSVA/B-preF, commonly known as MATISSE trial) which informed decisions to license the vaccine, mainly enrolled pregnant women (and their offspring) in upper-middle- and high-income countries; Only two African countries, South Africa and the Gambia participated in the trial and enrolled 13.0% (964 pregnant women) and 2.6% (196 pregnant women) of the total 7358 women enrolled globally. Also, the main vaccine study was undertaken during the COVID-19 pandemic, during which time there was interruption in transmission of RSV, therefore fewer events of severe RSV disease were detected even among young children born to mothers who were in the comparative group for the vaccine study. Moreover, additional analysis of the MATISSE trial data identified higher rates of babies born before term (<37 weeks of pregnancy) in vaccine recipients (7.4%) compared with placebo (those who did not receive the real vaccine) (4.0%; 1.85 times higher rate) recipients in upper-middle income countries (UMIC), whilst the rates of babies born before term were similar between the vaccine and placebo recipients in women from countries classified as high-income (5.0% vs 5.1%), lower middle income (3.1% vs 5.9%) and low-income (2.6% vs 2.5%). Notably, the births before term were not temporally related to vaccine administration, occurred more than 30 days after vaccination, and were independent of the age/time of pregnancy at which women were vaccinated. Also, the difference in the rates clustered over a narrow period of time, which coincided with the surge in COVID-19 cases associated with the Delta dominant wave, rather than being consistent throughout the trial. Consequently, the World Health Organization Strategic Advisory Group of Experts on Immunization (SAGE), has recommended for additional studies of RSVA/B-preF vaccine in low- and middle-income countries (LMICs), to more comprehensively determine the public health value of vaccination of pregnant women with this new vaccine in protecting their young children through to six months of age against severe LRTI. Also, the study would provide further information on the safety of the vaccine in pregnant women from LMIC, including enrolment of pregnant women whose demographics is more generalizable to the general population, compared with the restrictive inclusion and exclusion criteria used for enrolment of women in the main vaccine trial which led to licensure of RSVA/B-preF. Moreover, further interrogation is warranted to determine whether the signal of higher rates of births before term in UMIC observed in the MATISSE trial is persistent outside of the COVID-19 pandemic, and the relevance thereof in African countries more generally. When mothers are infected with HIV and have malaria parasites in their placenta, these infections have been shown to interfere with transfer of antibodies against various pathogens, including RSV, across the placenta from the mother to the unborn baby. Therefore, this trial will further investigate this association by assessing RSV antibody response and the efficiency of antibody transfer in pregnant women without underlying infections compared to those infected with HIV or malaria. The main purpose of the RSV-IMPACT trial is to define the public health value of maternal RSV vaccination among infants through 6 months of age in terms of health-related and health-system outcomes, and to evaluate whether there is an excess risk of adverse birth outcomes (e.g., before term birth, low birth weight (<2500 grams) from maternal vaccination. The phase IIIb trial will be conducted after licensure of the RSV vaccine and will be undertaken in The Gambia, Kenya (KEMRI Siaya and Kilifi), Ghana and in South Africa. The trial will target 13,000 pregnant women overall (3000 in Kenya), between 24 and ≤36 weeks of pregnancy. Global enrolment will take place over a period of 18 months, throughout the year, and the live-births of the enrolled women will be followed up for at least a year after birth, with passive surveillance for LRTI efficacy endpoints through bi-weekly contacts. The findings from this trial will also inform the government of Kenya, and other LMICs, on prioritization of RSV maternal vaccination to protect infants up to 6 months of age from LTRI. 

Respiratory Syncytial Virus (RSV) is a highly contagious respiratory virus and a leading cause of hospitalization for lower respiratory tract infections (LRTIs) among infants and young children aged 0-59 months globally, contributing 30%-80% of all hospitalizations. In Kenya, respiratory disease surveillance systems indicate substantial disease burden due to RSV infection in children under 5 years of age, particularly among infants, and substantial excess mortality associated with RSV emphasizing impact on children under 5 years and adults over 50 years of age. Vaccination remains the only strategy for preventing severe RSV disease among high-risk populations. The RSVA/B-preF (Abrysvo™) vaccine has been shown to be safe in mother-infant dyads, and protective against severe RSV associated LRTI in infants. The RSVA/B-preF vaccine is now licensed for use in pregnant women in a number of high-income countries, and is currently being considered for licensure in other African countries. The vaccine has been licensed for pregnant women from 28 to 36 weeks of GA in South Africa and 24 to 36 weeks of GA in Ghana, The Gambia and Kenya. Nevertheless, the pivotal phase III study of RSVA/B-preF (commonly known as MATISSE trial) which led to vaccine licensure, mainly enrolled pregnant women (and their offspring) in upper-middle- and high-income countries. Only two African countries, South Africa and the Gambia participated in the trial and enrolled 13.0% (964 pregnant women) and 2.6% (196 pregnant women) of the total 7358 global sample size. Also, the MATISSE trial was undertaken during the COVID-19 pandemic, during which time there was significant interruption of RSV circulation globally, due to non-pharmacological interventions aimed at limiting transmission of SARS-CoV-2. Additionally, there was interruption of RSV seasonality compared with the pre-pandemic period. Consequently, lower than anticipated attack rates of RSV medically-attended LRTI (MA-LRTI) were observed through to six months of age even among infants born to placebo recipients in the trial. Moreover, post-hoc analysis of the MATISSE trial data identified higher rates of preterm birth in RSVA/B-preF (7.4%) compared with placebo (4.0%; RR: 1.85, p<0.05) recipients in upper-middle income countries (UMIC), whilst the preterm rates were similar between the vaccine and placebo recipients in women from countries classified as high-income (5.0% vs 5.1%), lower middle income (3.1% vs 5.9%) and low-income (2.6% vs 2.5%). Notably, the preterm births were not temporally related to vaccine administration, occurred more than 30 days after vaccination, and were independent of the gestational age at which women were vaccinated. Also, the difference in the rates clustered over a narrow period of time, which coincided with the surge in COVID-19 cases associated with the Delta dominant wave, rather than being consistent throughout the trial. Noting the limited representation of low- and middle-income countries (LMIC) in the pivotal phase III vaccine efficacy trial of RSVA/B-preF, as well as the trial having been done when there was a low force of RSV infection during the COVID-19 pandemic, the World Health Organization Strategic Advisory Group of Experts on Immunization (SAGE), has recommended for additional studies of RSVA/B-preF vaccine in LMICs, to evaluate the efficacy of RSVA/B-preF against severe RSV-LRTI and to more comprehensively determine the public health value of the vaccine. Also, further interrogation is warranted to determine whether the signal of higher preterm births in UMIC observed in the MATISSE trial is persistent outside of the COVID-19 pandemic, and the relevance thereof in African countries more generally. Moreover, maternal HIV infection and placental malaria have been linked to impaired transplacental transfer of IgG antibodies against various pathogens, including RSV. Therefore, this trial will further investigate this association by characterizing the neutralizing antibody (nAb) response and the efficiency of transplacental IgG transfer in pregnant women without underlying infections compared to those infected with HIV or malaria. The main purpose of the RSV-IMPACT trial is to define the public health value of maternal RSV vaccination among infants through 6 months of age in terms of health-related and health-system outcomes, and to evaluate whether there is an excess risk of adverse birth outcomes (e.g., preterm birth, low birth weight) from maternal vaccination. The phase IIIb trial will be conducted post-licensure of the RSV vaccine and will be undertaken in The Gambia, Kenya (KEMRI Siaya and Kilifi), Ghana (two sites) and in South Africa (5 sites). The trial will target 13,000 pregnant women overall (3000 in Kenya), between 24 and ≤36 weeks of gestational age. Enrolment will take place over a period of two years, throughout the year, and the live-births of the enrolled women will be followed up for at least a year after birth, with passive surveillance for LRTI efficacy endpoints through bi-weekly contacts. The findings from this trial will also inform the government of Kenya, and other LMICs, on prioritization of RSV maternal vaccination to protect infants up to 6 months of age from LTRI.