The Oxford-AstraZeneca vaccine: What is the optimal time interval between the primary and booster doses? Would a single dose be efficacious?

Background

The Oxford-AstraZeneca vaccine against COVID-19 infection has been approved and extensively used in several countries, including India. In contrast to the earlier recommendation to administer the primary and booster doses 4 weeks apart based on previously published randomized controlled trials, the UK has adopted an approach of administering the vaccine in two doses at a 12-week interval. There has been increasing interest in the validity and efficacy of this approach, considering delays in vaccine delivery in many parts of the world. It is against this background that the Oxford University researchers evaluated the efficacy of a single dose and a delayed booster dose of the Oxford-AstraZeneca vaccine. The present study is a sequel to the original report published previously, including subjects from four randomized controlled trials – two in the UK, and one each in Brazil and South Africa.1

In the interim analysis published earlier, 11,636 subjects were included in the primary efficacy analysis between April 23 and Nov 4, 2020.2 The present analysis follows an additional month of data collection, including 17178 subjects. This report includes data on 332 cases with primary symptomatic COVID-19, compared to 131 cases in the original report. Besides, it includes data from an additional month of follow-up. 

The trials were initially planned as single-dose vaccination. In the meantime, phase I studies showed enhanced immunogenicity with two doses. Hence, the dosing was subsequently modified to a two-dose regimen. However, some study subjects opted not to receive the second dose, providing the opportunity to study the efficacy of a single dose of vaccine. Besides, the second dose was administered later than originally planned in many subjects due to manufacturing delays. Delayed administration of the second dose allowed evaluation of the efficacy of two doses administered at different time intervals. The study also includes evaluation of data from an additional month of enrollment and follow-up after the initial interim analysis. 

Methods

The pooled analysis included four studies, including a phase 1/2 and a phase 2/3 from the UK, a phase 3 study in Brazil, and a double-blind phase 1/2 South African study. Subjects were randomized in a 1:1 design to receive the vaccine or placebo. In the UK phase 2/3 study, a subgroup of patients inadvertently received a low dose as the first vaccine dose, followed by a standard dose. Among the 17178 subjects included in the primary efficacy analysis, 8597 received the vaccine and 8581 received placebo. Patients were followed up beginning at least 14 days after the second dose. 

Primary outcome

The primary outcome was the development of “primary symptomatic” COVID-19, defined as at least one of 5 pre-defined COVID-19 symptoms with virological confirmation by nucleic acid amplification test. This included cases that occurred more than 14 days following the second dose of the vaccine. The overall efficacy with two doses was 66.7% (95% CI: 57.4–74%). The efficacy appeared to be more pronounced among patients who received a low dose-standard dose regime in the UK phase 2/3 of the study (Table 1). However, the number of patients who received the low-dose standard dose regime was small, and the confidence intervals overlapped. 

Table 1. Vaccine efficacy in the prevention of primary symptomatic infection 

 Total number of cases Vaccine Control Efficacy with 95% CI
Overall 33284/8597 (1·0%)248/8581 (2·9%)66·7% (57·4–74·0)
Standard dose-standard dose27174/7201 (1·0%)197/7179 (2·7%)63·1% (51·8 to 71·7)
Low dose-standard dose 6110/1396 (0·7%)51/1402 (3·6%)80·7% (62·1 to 90·2)

Secondary analysis 

In the UK arm of the trial, the weekly nose and throat swabs from volunteers were performed to check for infection. The secondary analysis included asymptomatic patients and those with non-predefined symptoms, and all patients who tested NAAT positive (Table 2). 

Table 2. Vaccine efficacy in the prevention of asymptomatic infection and NAAT positive cases 

 Total number of cases VaccineControl Efficacy with 95% CIComment
Asymptomatic or non-predefined symptoms 13057/4071 (1.4%)73/4136 (1.8%)22·2% (–9·9 to 45·0)No protection against asymptomatic infection 
All NAAT positive cases507161/8597 (1.9%)346/8581 (4.0%)54·1% (44·7 to 61·9)Potential for reduction of transmission 

The vaccine demonstrated 100% efficacy in preventing the requirement for hospital admission due to COVID-19 infection beginning 22 days after the first dose. None of the subjects who received the vaccine required hospital admission, compared to 15 who required admission in the control group. 

Exploratory outcomes 

This follow-up study addressed two important questions. Is a single dose of the Oxford-AstraZeneca vaccine efficacious? Would delaying the second dose enhance efficacy compared to the initial recommendation of a 28-d interval between doses?  

Single-dose efficacy

The researchers evaluated disease occurrence starting from 21 days after a single dose. These were subjects who opted out of receiving the second dose during the initial phase of the study. During a 90-day follow-up period, 88 COVID-19 infections occurred after a single dose; 17/9257 (0.2%) were in the vaccine group compared to 71/9237 (0.8%) in the control group.  Based on this data, a single standard vaccine dose of vaccine demonstrated an efficacy of 76·0% (95% CI 59·3 to 85·9) in protecting against primary symptomatic COVID-19 infection during a follow-up period of 90 days. (Table 3). 

Table 3. Vaccine efficacy after a single dose 

Follow-up period after single dose Total number of cases VaccineControl Efficacy
22 to 90 days8817/9257 (0.2%)71/9237 (0.8%)76·0% (59·3 to 85·9)

A single dose of vaccine showed a 63·9% efficacy CI (46·0 to 75·9) against any NAAT-positive infection from 22 days to 90 days. This suggests the potential for a reduction in disease transmission. However, no efficacy was demonstrated against asymptomatic infection during the same period.

Varying time intervals between first and second dose

The authors also evaluated the effect of a variable time interval between the first and the second dose. This study included patients who could not be administered the second dose at the scheduled time due to manufacturing delays. 

Vaccine efficacy was evaluated at dosing intervals of less than 6 weeks, 6–8 weeks, 9–11 weeks, and 12 weeks or more. Efficacy appeared to be least when the dosing interval was less than 6 weeks; it progressively increased with a delayed second dose of up to 12 weeks or more. Among patients who received standard dose-standard-dose or the low-dose standard-dose regime, vaccine efficacy was 80% if the dosing interval was 12 weeks or more, compared to 55.1 efficacy if the dosing interval was less than 6 weeks (Table 4). 

Table 4. Vaccine efficacy at varying time intervals between the primary and the booster dose 

Dosing interval Vaccine Control Efficacy 
Less than 6 weeks35/3905 (0·9%)76/3871 (2·0%)55·1% (33·0 to 69·9)
6–8 weeks20/1124 (1·8%)44/1023 (4·3%)59·7% (31·7 to 76·3)
9–11 weeks14/1530 (0·9%)52/1594 (3·3%)72·2% (50·0 to 84·6)
More than 12 weeks15/2038 (0·7%)76/2093 (3·6%)80·0% (65·2 to 88·5)

Serious adverse events 

Serious adverse events were rare; 108 of 12 282 (0·9%) subjects in the vaccine group and 127of 11 962 (1·1%) subjects in the control group experienced serious adverse events.

Summary 

  • This study is a sequel to the preliminary report published earlier and evaluated the efficacy of the vaccine after another month of data collection
  • The Oxford AstraZeneca vaccine appears to be efficacious in preventing symptomatic COVID-19 infection
  • The investigators evaluated the efficacy of a single dose of vaccine and variable time intervals between the primary and booster dose as part of a post-hoc exploratory analysis 
  • A single dose appears to be efficacious from 22–90 days after administration
  • Vaccine efficacy appears to be superior with a longer interval of 12 weeks or more between doses compared to the initial recommendation of 28 days. 
  • It is important to note that the study was not designed to evaluate a single dose or varying time intervals between doses. Recipients of a single dose were younger, predominantly females, and mostly healthcare workers, which may have confounded the results. Besides, subjects who received a single dose were followed up for a longer period of time, resulting in a possible bias. 
  • Further detailed evaluation is required to assess the efficacy of a single dose and the optimal time interval between the primary and the booster dose

References

1.         Voysey M, Clemens SAC, Madhi SA, et al. 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. The Lancet. 2021;0(0). doi:10.1016/S0140-6736(21)00432-3

2.         Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet. 2021;397(10269):99-111. doi:10.1016/S0140-6736(20)32661-1

1 thought on “The Oxford-AstraZeneca vaccine: What is the optimal time interval between the primary and booster doses? Would a single dose be efficacious?”

  1. Thank you sir for this well compiled blog. Govt. in INDIA is pushing for 28 days interval compromising efficacy. Just Hope that would change in the future.

Leave a Reply to sudhindra pk Cancel reply