Effectiveness of Trivalent Inactivated Influenza Maternal Vaccination Among Pregnant Women and Their Newborns in South Africa

Study design Investigators will conduct a vaccination campaign amongst pregnant women in different areas of South Africa and monitor the effectiveness of the programme. Investigators will then use an unmatched case-control study design.

Vaccination campaigns will be conducted in clinics with active promotion of influenza vaccination. Posters will be placed in clinics recommending influenza vaccination for pregnant women and health education material will be provided. Vaccines will be administered by clinic staff through routine services as vaccination is the recommended standard of care. Dedicated study staff (research assistants) will be placed in each clinic offering vaccination. These staff will assist clinic staff with management of influenza vaccine supplies and documentation of influenza vaccination status in patient records. Vaccination status will be documented in the mother's antenatal records. Investigators will visit all the facilities in the area serving the surveillance hospital and conduct staff training in the facilities where babies are delivered to enter maternal influenza immunization status on the child's vaccination card at the time of administration of the birth dose of polio vaccine.

Identification and enrolment of cases and controls for the estimation of VE against laboratory-confirmed influenza-associated hospitalised illness in infants<6 months of age overall and by HIV status Cases and controls will be identified through active sentinel surveillance for hospitalised medical illness of any diagnosis amongst children aged <6 months. Hospitals where surveillance will be conducted will be large hospitals serving the communities in which the antenatal TIV campaign will be conducted. Investigators will conduct ongoing active surveillance with consecutive patient selection until the required sample size is reached.

Identification and enrolment of cases for monitoring adverse events Dedicated study staff will conduct an information session with women selected for enrolment. These women will be asked for written informed consent prior to participation and non-participation will not affect a woman's eligibility to receive vaccine. Following vaccination administered by the nurse, as per the Department of Health schedule, demographic information, medical history, obstetric history and contact details will be collected from each participant by structured interview. Immediate reactions to the vaccine will be recorded at the time of interview. A separate aide de memoire diary will then be given to each participant. This diary will assist the women to record symptoms experienced in the seven days following vaccination. The symptoms listed will be based on standard collection tool.

Data collection Hospitalised children <6 months For hospitalised children <6 months of age, epidemiologic data will be collected from a parent or caregiver interview, if possible, as well as review of medical and vaccination records of mother (antenatal cards, maternal in-patient cards and antenatal clinic registers) and baby (Road-to-Health cards and clinic registers). Information gathered will include: demographics of mother and baby (age, sex, race), medical history of baby (premature birth, congenital illnesses such congenital heart or lung disease, immunosuppressive or other chronic illness), recent infections, recent antimicrobial use, household characteristics (residence type and number of rooms, number of persons and their ages, questions related to socioeconomic status, exposure to tobacco smoke and indoor air pollution), child-care centre attendance, breast feeding and vaccination history. It will also request educational level of the parent or guardian and if adults or other children in the household had received pneumococcal or influenza vaccines. Information on HIV status will include whether the mother was tested for HIV during pregnancy and her HIV status if tested, whether the patient has been previously tested for HIV and results of such tests, history of underlying illness and previous HIV-associated diagnosis. Nutritional status of the child will be evaluated measuring weight (in kilograms) and length (in centimetres) at the time of admission. If the parent or guardian has a written vaccination record for the case or control child, names, batch numbers and dates of vaccines will be recorded (see determination of vaccination status below). For issues that may change with time (e.g. exposure to cigarette smoke, breastfeeding, day-care attendance), the questions will focus on the 4 weeks (as in 30 or 31 days) before illness.

Adverse birth outcomes For the effectiveness against adverse birth outcomes (prematurity, LBW and SGA) epidemiologic data will primarily be collected from birth records and maternal antenatal records. Information gathered will include: demographics of mother and baby (age (of mother), sex, race), household characteristics (residence type and number of rooms, number of persons and their ages, questions related to socioeconomic status. It will also request educational level of the parent or guardian. Information on HIV status will include whether the mother was tested for HIV during pregnancy and her HIV status if tested. The baby's birthweight and gestational age will be evaluated from delivery and antenatal records. Birthweight (in kilograms) and length (in centimetres) will be documented.

Hospitalised pregnant women and postpartum women, ≥18 years Epidemiologic, clinical presentation, laboratory data as well as information on hospital course will be collected from enrolled patients. A case investigation form will be completed by structured interview. Information gathered will include: demographics (age, sex, race), presenting symptoms, medical history (lung disease, immunosuppressive or other chronic illness including cardiac diseases, chronic renal diseases, diabetes mellitus and similar metabolic disorders), previous hospital admissions, recent infections, recent antimicrobial use, household characteristics (residence type and number of rooms, number of persons and their ages, questions related to socioeconomic status, exposure to tobacco smoke and indoor air pollution) and data on current and previous influenza vaccination. Information on HIV status will include current HIV status and whether the patient has been previously tested for HIV and results of such tests, previous HIV-associated diagnosis, HIV staging. Obesity evaluated measuring weight (in kilograms) and length (in centimetres) at the time of admission. Medical records will be reviewed for inpatient management (antimicrobial use, influenza antiviral therapy and results of investigations conducted) and outcome (admission to ICU, discharged or died).

Monitoring adverse events The diary will be taken home by the participant. Telephone contact will be made with the participant by a study staff member on day eight (or day 7, 9 or 10 if day 8 falls over a weekend) and the contents of the diary will be recovered telephonically. If the study staff are not able to contact the participant on the first attempt, three further documented attempts will be made to contact the patient. Participants will also be request to return their diaries at their next clinic visit. Participating women will be asked to contact the study team if she is hospitalized for any reason in the seven days post-vaccination. A member of the study team will visit the woman in hospital and, using a predesigned form, collect data on the reason for hospitalization.

Logs recording the enrolled patients with their contact details will be kept at each site. Completed data collection forms will be returned to the data centre at NICD for data capture and storage.