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

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 "adaptive" 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 "long" dosing intervals is superior to that following immunisation at "short" dosing intervals. Preg-CoV is designed as a single-blind, randomised, phase II multi-centre study. Eligible participants will be healthy pregnant women ≥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.