Early safety and immune responses in older people using the Oxford vaccine: overall results complicated by dosing error

On 18 November 2020, the Lancet published initial safety and immunology results from a substudy of older adults enrolled in the phase2/3 ChAdOx1 vaccine study, together with a supportive editorial comment. [1, 2]

However, the main study results are also controversial for reporting higher efficacy in participants who, by error were only given a lower dose of the two-dose vaccine. [3]

Slightly fewer side effects (mainly local injection reactions and tiredness after the vaccine) were reported by the older participants receiving the active injection (200 aged >70, 120 aged 55 to 69, and 100 aged 18 to 54). Serious side effects will continue to be monitored for a year.

Overall, >99% of participants who received both an initial and boost vaccination generated neutralising antibodies by day 14,

Although these results are encouraging, the study included very few participants older than 80 years and people with substantial underlying chronic illnesses and frailty were also excluded.

The study concludes that summarise that this vaccine is better tolerated in older adults and has similar immunogenicity across all age groups after a boost dose.

Efficacy results from this substudy are still pending.

However, top-line results reporting overall efficacy in a press release from AstraZeneca are controversial. Overall efficacy (in >11,600 participants) was reported at 70%, but this increased to 90% in participants (n=2,741) whose first dose, used a half rather than full dose. When both doses were given at the full dose, also one month apart, efficacy was only 62%. [3]

This is controversial because the half-dose given to participants in the UK study was not planned but occurred as an error. Although the mistake was reported to the regulatory authorities at the time and the study was allowed to continue, actually producing better results, this changes the scientific approach of the overall analysis. [4]

A further complication, not reported as widely, was that median time to the second dose of the vaccine was 12 weeks rather than the planned 4 weeks. This further complicates the analysis to explain higher response rates in the group.

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It is currently unclear whether regulatory agencies, both in the UK and the US will require additional results from ongoing studies have used the initial half-dose as part of the study design.

This is unfortunately given the many practical advantages of the Oxford candidate, including easier transport (no need for cold chain) and proposal for the price to be much lower.

References

1. Ramasamy MN et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single blind, randomised, controlled, phase 2/3 trial. Lancet. DOI: 10.1016/S0140-6736(20)32466-1. (18 November 2020).
   https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32466-1/fulltext
2. Andrew MK et al. Age and frailty in COVID-19 vaccine development. (18 November 2020).
   https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32481-8/fulltext
3. AstraZeneca press statement. AZD1222 vaccine met primary efficacy endpoint in preventing COVID-19. (23 November 2020).
   https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html
4. Lawton G. New Scientist. Do Oxford/AstraZeneca covid-19 vaccine results stand up to scrutiny? (27 November 2020).
   https://www.newscientist.com/article/2261092-do-oxford-astrazeneca-covid-19-vaccine-results-stand-up-to-scrutiny

This article was first posted on 27 November 2020.