Delaying 2nd Oxford COVID-19 vaccine dose may boost efficacy: Lancet
UK: A 3-month interval between versus 6-week interval between Oxford COVID-19 vaccine results in higher vaccine efficacy, finds a recent study in the journal Lancet. With a 3-month interval, the first dose offers 76% protection.
The findings suggests that the interval between the two doses can safely be extended to 3 months safely given the protection offered by a single dose. This may allow countries to vaccinate a large proportion of the population more rapidly.
The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency for emergency use. It has a regimen of two standard doses given with an interval of 4–12 weeks. The planned roll-out in the UK involves vaccination of people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later.
Merryn Voysey, University of Oxford, Oxford, UK, and colleagues in this study, provided a further prespecified analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, the researchers showed the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.
Study lead author Professor Andrew Pollard, University of Oxford, UK, says: "Vaccine supply is likely to be limited, at least in the short term, and so policy-makers must decide how best to deliver doses to achieve the greatest public health benefit. Where there is a limited supply, policies of initially vaccinating more people with a single dose may provide greater immediate population protection than vaccinating half the number of people with 2 doses. In the long term, a second dose should ensure long-lived immunity, and so we encourage everyone who has had their first vaccine to ensure they receive both doses."
Following the regulatory approval of a vaccine, it is important to understand the best dose interval to ensure optimal roll-out of the vaccine. Factors associated with this include the effect of different intervals on protection after the second dose, and the risk of infection between doses either due to lower efficacy of a single dose or rapid waning of efficacy while waiting for the second dose.
To understand these factors, the authors combined data from randomised controlled trials in the UK, Brazil, and South Africa, including 8,948, 6,753, and 1,477 people, respectively (totalling 17,178 people). Participants were aged 18 years and over, and either received two standard doses of the Oxford COVID-19 vaccine (8,597 participants) or a control vaccine/saline placebo (8,581). In the UK trial, a subset of participants (1,396 people) received a lower dose of the vaccine as their first dose.
The primary outcome of the trial was the number of symptomatic COVID-19 cases (confirmed by positive COVID-19 test, and having fever, cough, shortness of breath, loss of smell or loss of taste) in the control and COVID-19 vaccine groups occurring more than 14 days after the second dose.
Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine).
Key findings of the study include:
- The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose.
- Overall vaccine efficacy more than 14 days after the second dose was 66·7%, with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group.
- There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events.
- There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group.
- Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0%.
- Modelling analysis indicated that protection did not wane during this initial 3-month period.
- Antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66).
- In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% at <6 weeks).
- These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18–55 years (GMR 2·32).
Study author, Dr Merryn Voysey, University of Oxford, UK, says: "This latest analysis confirms our previous findings of the higher efficacy of a low- then standard-dose regimen. However, with additional data available, we have found that the enhanced efficacy and immunity may be partly driven by the longer interval between doses that was common in this trial group. This further supports the relationship we have found between vaccine interval and efficacy in those receiving two standard doses, which is the preferred regimen because there are more data to support its use, and because it is simpler to deliver a vaccine programme when the same vaccine is given for both doses.
Professor Pollard says: "It is important to understand whether vaccines can reduce COVID-19 transmission. While specific transmission studies were not included in our analysis, UK trial participants were tested for COVID-19 each week regardless of symptoms, and we combined this with other positive COVID-19 cases in the trial to help determine the overall impact of the vaccine on risk of infection. If the vaccine had no impact on transmission, we would expect that the number of positive tests in our trial would be the same in vaccine and control groups. This is because the vaccine would convert severe cases to mild cases, and mild cases to asymptomatic cases. However, we saw a reduction in the overall number of positive cases, which indicates that the vaccines may reduce infections. Real-world assessments of how the vaccine is working in the population will be needed to confirm this preliminary result."
The study titled, "Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials," is published in the journal Lancet.