Lay Title: A study to assess the safety of a RSV vaccine in pregnant women and its ability to protect their babies from severe infection of the breathing systems.

What is the problem/background?
Respiratory Syncytial Virus (RSV) is a virus that has now become one of the main causes of severe infection of the breathing systems (known as Lower Respiratory Tract Infection or LRTI) which leads to hospitalization among infants under 6 months of age.
A vaccine is now available for use in pregnant women to protect infants from getting severe disease when infected with RSV, in developed countries. However, the clinical trial which led to approval of this vaccine for use, mainly enrolled pregnant women (and their babies) in developed countries such as Europe and the United States of America (USA) and only two countries in Africa (South Africa and The Gambia) were involved. Additionally, the trial was conducted during the COVID-19 pandemic, during which time there was interruption in spread of the RSV virus. As a result, the World Health Organization, has recommended for additional studies of the RSV vaccine in developing countries such as Kenya, to determine whether vaccination of pregnant women protects infants against severe infection of the breathing systems and is safe. This proposed trial will therefore be conducted in multiple countries including South Africa, Ghana, The Gambia and in Kenya (Kilifi and Siaya), to assess safety of the vaccine in pregnant women and its efficacy in preventing against severe infection of the breathing systems caused by RSV among infants. The study will enrol women during pregnancy, administer the vaccine between 6 to 8 months of pregnancy and follow them up through to the end of their pregnancy; as well as follow-up their live babies for lower breathing systems infection episodes which would be investigated for RSV infection.

What questions are we trying to answer?
The rationale for this study is to evaluate the safety of a RSV vaccine in pregnant women and its protection against severe infection of the breathing systems among infants through to six months or up to 2 years of age, depending on the time of enrolment. We are therefore asking, is the RSV maternal vaccine safe among pregnant women in Kilifi Kenya? and are infants born from vaccinated mothers protected from getting severe disease of the breathing systems caused by RSV infection?

Where is the study taking place, how many participants does it involve and how are they selected?
This is a multi-country trial in Africa, which will be undertaken in The Gambia, Ghana , Kenya (Kilifi and Siaya) and in South Africa (see details in the Master Protocol in Appendix 23.1). In Kilifi, this study will take place within the Kilifi Health and Demographic Surveillance System (HDSS) area households and in 6 health facilities (Matsangoni, Mtondia, Mavueni, Pingilikani, Vipingo and Kilifi County Referral Hospital-where there is an ongoing surveillance for respiratory viruses). The study will involve 1500 pregnant women, assigned in the ratio of 1:1 between those who will receive the RSV vaccine and those receiving a mock “vaccine”(placebo). Participants will be identified by study staff as early as 3 months of their pregnancy at antenatal clinics (ANC) of the six participating facilities as they attend for care or traced in the households using HDSS pregnancy register. Identified pregnant women will be given a verbal invitation to attend a consenting and screening session at Kilifi County Referral Hospital (KCRH). Those eligible and who consent to the trial, will be enrolled for participation. Enrolment will be based on “first come first served basis” and will continue until the target sample size is reached.

What does the study involve for those who are in it?
After potential participants have been identified, they will be consented. For those who will agree to participate in the trial, they will be screened for eligibility. During screening, pregnant women will be asked questions about their health and their medical records will be reviewed to make sure they are suitable for enrolment. A scan will be used to confirm the size of the pregnancy. If an ultrasound scan is not available during the current pregnancy, it will be conducted as part of the screening procedures. All eligible women between 6th to 8th month of pregnancy will be enrolled and assigned to either a vaccine or a non-vaccine group. Participants will be vaccinated on the same day as the day of enrolment. A 10ml blood sample will be collected from the participant during enrolment before vaccination. All trial procedures for enrolment and vaccination will be conducted at KCRH. Enrolled participants will be followed up passively by study staff through phone calls once every two weeks before (8 months) 36 weeks of pregnancy and thereafter daily phone calls till delivery to document any occurrence of illness or events during pregnancy. Participants will be required to confirm if they have intention to deliver at KCRH, Vipingo or Matsangoni health Centre where study procedures can be conducted. During delivery, a placental tissue, a total of 10ml of (i.e. 2 teaspoons) cord and a maternal blood sample (10 mls) will be collected. Those who will deliver in other facilities other than KCH, Vipingo or Matsangoni, will be asked to provide details of the delivery place and events which occurred during delivery through a scheduled phone call and information confirmed through the medical records during a scheduled home visit or in case they come for a sick visit. Attempts will be made to visit the participant within 72 hours if delivery occurs outside of the designated health facilities. At this visit, both physical examination and weighing of the neonate will be conducted.
After delivery, the mother will be followed up until 6 weeks after birth (recovery period) while the baby will be followed up for a maximum period of 6 months to 2 years depending on the time of enrolment into the trial. Post delivery follow-up will be conducted once every two weeks for the first 6 months, and thereafter monthly until 2 years, depending on the time of enrolment. Follow up will be done through phone call and/or home visits to monitor for any illness. On the 6th month of infant follow up, all participants will be visited at home. Participants will be asked to come to the study clinic or bring the baby to the study clinic if they notice any signs of illness. A nasal sample will be collected from the infant in the event they are hospitalized or present at the outpatient clinic with a respiratory illness and tested for RSV infection.

What are the benefits and risks/cost of the study for those involved?
Benefits:
i. Participants will receive feedback on status of their pregnancy during enrolment into the study.
ii. In the event a participant (mother/infant) falls ill during the period of follow up, the study will cover costs for drugs for common acute illnesses, if they attend our study clinics.
Risks/Inconveniences: During the collection of respiratory and blood specimens, there may be slight discomfort. Enrolment may take about 5 hours. Answering follow-up phone calls may take about 3 minutes of participant's time, while the 6th month home visit will take about 50 minutes.
Compensation: Participants will be given a meal and an out-of-pocket allowance amounting to KSHS 500 and reimbursed transport costs based on public transport during enrolment session. During delivery, participants will be given a baby package consisting of 1 packet of 8 diapers, a baby shawl and a piece of bar soap. If referred to KCRH for infant’s sick visit and collection of nasal swab sample, participants will be reimbursed for their transport costs based on public transport and given an out-of-pocket allowance amounting to KSHS 500. During the 6th month follow-up visit, participant will be given a token of appreciation consisting of 1 packet of diapers amounting to about KSHS 500.

How will the study benefit society?
Benefits to society are anticipated in the future. The results of this trial may guide roll out of the vaccine in Kenya and other countries in Africa. The society may benefit from this trial by the implementation of the maternal RSV vaccine as part of the standard of care. The wider society may benefit from the reduction on RSV associated illness in infants.

When does the study start and finish?
This study will begin once ethical approval is obtained and will last for 26 months.

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infection (LRTI) which leads to hospitalization among infants worldwide, with the highest burden occurring in the developing countries. A maternal vaccine RSVA/B-preF vaccine from Pfizer is now licensed for use in a number of high-income countries. Marketed as Abrysvo™, the RSVA/B-preF vaccine has obtained regulatory approval in South Africa, Ghana, Gambia and in Kenya.
The World Health Organisation (WHO) Scientific Advisory Group of Experts on Immunisation (SAGE), have recommended post licensure efficacy evaluation of the RSVA/B-preF vaccine in LMICs and administration of the maternal RSV A/B-preF vaccine within the 3rd trimester of pregnancy (i.e. from 27-28 weeks of GA onward). This is because, the phase III clinical trial which led to vaccine licensure, mainly enrolled pregnant women (and their offspring) in upper-middle and high income countries. The study was also undertaken during the COVID-19 pandemic, during which time there was interruption in transmission of RSV, yielding lower than anticipated attack rates of RSV LRTI even among infants born to placebo recipients in the study. The trial results showed an increased preterm rate in vaccine compared with placebo recipients and this was observed only in upper middle income countries and not in HIC or low-income countries. The clustering of cases of preterm births in the upper-middle income countries, coincided with the surge in COVID-19 cases associated with the Delta dominant wave and somewhat less so when the Omicron wave dominated. The proposed phase IIIb RSV-IMPACT trial in low and middle income countries (LMICs), therefore aims to comprehensively define the public health value of maternal RSV vaccination among infants through 180 days of age in term of health-related and health-system outcomes, and particularly in an era where RSV epidemiology is now similar to the pre-COVID-19 era. Also, the study will evaluate whether there is an excess risk of preterm birth from maternal RSVA/B-preF vaccination. The planned trial will be conducted in multiple sites in four Countries in Africa: The Gambia, Ghana, Kenya (Kilifi and Siaya, 1500 women at each site) and in South Africa. The RSV impact trial will be conducted post-licensure of the RSV vaccine in Kenya and the other participating countries. Pregnant women will be randomly assigned in a 1:1 ratio to either receive RSVA/B-preF vaccine or a placebo. Findings from this trial may help inform decision to the roll-out of maternal RSV immunization in Kenya and within LMICs at large.