Title: A Phase II, randomised, single-blind, platform trial to assess safety, reactogenicity and immunogenicity of COVID-19 vaccines in pregnant women in the United Kingdom
Funder: Department of Health and Social Care

Abstract: Although the risk to pregnant women following COVID-19 infection is generally low, there is a 2-3 fold increased risk of preterm birth for women with symptomatic COVID-19 and recent analysis of a large registry indicates that pregnant women are more likely to be admitted to an intensive care unit with COVID-19 than age-matched non-pregnant women. The current JCVI advice is that COVID-19 vaccines should be offered to pregnant women at the same time as the rest of the population, based on their age and clinical risk group. However, as pregnant women were specifically excluded from trials of COVID-19 vaccines, there are important and unanswered questions regarding the safety, immunogenicity and persistence of immunity in the vaccinated pregnant woman and her infant, as well as the optimal vaccination schedule to be used in this population. Using an &quot;adaptive&quot; platform design Preg-CoV will address these questions for current vaccines, as well as for new vaccines as they are approved. The primary objective of Preg-CoV is to determine whether the immune response at delivery (anti-S protein IgG concentrations) following immunisation with COVID-19 vaccines at &ldquo;long&rdquo; dosing intervals is superior to that following immunisation at &ldquo;short&rdquo; dosing intervals. Preg-CoV is designed as a single-blind, randomised, phase II multi-centre study. Eligible participants will be healthy pregnant women &ge;18 years of age, between 13 and 34 weeks gestation on the day of planned vaccination, with an uncomplicated, singleton pregnancy, no known increased risk for complications of pregnancy and no contraindication to the vaccines in the study. Women will be randomised to receive 2 doses of vaccines at either short (4-6 weeks) or long intervals (8-12 weeks). In the 28 to 34 week cohort, the 2nd dose will be provided after delivery, allowing the impact of one dose in pregnancy to be assessed. In the main (13-24 week) cohort, participants will receive a routine pertussis-containing vaccine at one of the visits; this will facilitate blinding of the schedule. A separate cohort will establish the response to a single dose in those who received one dose before pregnancy. All participants will have blood tests performed at baseline and 2-4 weeks post first and second doses, at delivery and at 12 months. Infants will have blood tests at day 0 (cord) and one further sample at either 6 or 12 weeks (via randomisation) to assess antibody kinetics. Breast milk samples will be obtained in a sub-group. The main immune outcomes will be the anti-Spike and anti-nucleocapsid immunoglobulins, neutralising antibodies, cellular immune responses, IgA and IgG against SARS-CoV-2 in breast milk (in a subgroup). Reactogenicity will be assessed through use of an electronic diary for 7 days post vaccination and a range of safety outcomes will be collected including pregnancy, including neonatal outcomes of special interest and infant development at 12 months. 200 participants will be recruited per vaccine included in the main cohort (100 in each arm). By collecting these data in a systematic and controlled manner we aim to inform evidence-based guidance for optimal vaccination of pregnant women.

Lay abstract: What is this trial aiming to find out? The Preg-CoV trial aims to identify the best interval to be used between doses of COVID-19 vaccines for protecting pregnant women against COVID-19. Why are we doing this study? Studies have found that pregnant women are more likely to develop severe COVID-19 disease and to die from COVID-19, compared to non-pregnant women. Pregnant women who develop COVID-19 symptoms are also around two times more likely to have their babies early. For these reasons, the current UK national guidance is that two doses of COVID-19 vaccines should be offered to pregnant women at the same time as the rest of the population. However, further pregnancy-specific research is needed on COVID-19 vaccines, such as the best interval to be used between these 2 doses. The trial design The trial will compare vaccines that are currently being used in the UK vaccination programme, as well as new vaccines as they are approved. Pregnant women aged 18 years or older and 13-34 weeks gestation can be considered for enrolment into the study. Once they have given their consent, participants will be randomised to receive two doses of a COVID-19 vaccine (or only one dose if the participant has already received their first dose prior to the study), in a short-time interval (4-6 weeks) or a long-time interval (8-12 weeks). For some participants this means they will receive their second dose after delivery. Participants will be blinded to the vaccine they receive. The majority of participants will also be blinded to the interval between doses. This will be done by incorporating the routine pertussis (whooping cough) vaccine into the trial schedule. Participants will be followed up until one year after delivery. Several blood samples will be taken from participants throughout the study. A cord blood sample will also be taken after delivery in a subset; this sample is taken from the umbilical cord after the baby has been born and the cord has been cut; it is not taken from the baby. A baby blood sample will then be taken at six - twelve weeks of age. Participants will be asked to complete a symptom diary and to report any significant medical events. For a sub-group, breastmilk samples will also be collected. Public engagement and dissemination The plans for this trial have been discussed with our PPI research group which is made up of pregnant women, those who have recently had a baby, and their partners, and they provided input on the design of the trial. Results of the trial will be disseminated in peer-reviewed scientific journals, conference presentations and online publications and will inform national guidelines for optimal protection of pregnant women.

Research activity codes: 3.4 VACCINES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION