AstraZeneca’s covid-19 (mis)adventure and the future of vaccine equity
BMJ 2022; 379 doi: https://doi.org/10.1136/bmj.o2592 (Published 11 November 2022) Cite this as: BMJ 2022;379:o2592
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Dear Editor
Like vaccine equity, equity of access to some of the antiviral medications remains an elusive goal, even for antivirals which can be taken orally, without specialised medical supervision. In the clinical study context it all seems very straightforward, as was the case in the Israeli study where eligibility for inclusion in the study evaluating paxlovid efficacy comprised one or more of the following risk factors:-
Age 60 or more, diabetes, obesity, hypertension, current smoking, chronic lung disease, cardiovascular disease, chronic kidney disease, chronic liver disease, malignancy, and immunosuppression, respectively[1].
In the real world, however, "using these antivirals .....will be challenging, since their availability will be low across almost all countries for some time"[2[.
For example, in the USA, in order to qualify for a prescription you must have had a positive test result....and you must either have certain underlying conditions (including obesity, diabetes, cancer or others) or be 65 or older[3], whereas, in the NHS , only those who are in the highest risk groups are eligible[4],[5]. The highest risk group includes patients with malignancy and those with immunosuppression and rare neurological disorders, but does not include some of the risk factors such as age 60 or more, obesity, hypertension, diabetes, cardiovascular disease, and chronic lung disease, notwithstanding the inclusion of those disorders in the Israeli study[1].
Ethical issues generated by variability of eligibility criteria include the following:-
Should immunocmpromised patients always have priority over any other nonimmunocompromised patients eligible for any of the antivirals?
Should patients with two risk factors (eg obesity and diabetes) be prioritised over those with one risk factor (eg age >60 years)? [2].
In the context of the wider world, there seems to be a sense that paxlovid might be a game changer requiring prioritisation of its distribution. Accordingly, a new public-private group, called the COVID Treatment Quick Start Consortium, has been launched to provide oral antiviral treatments for COVID-19 in 10 low-and middle-income countries (LMICs)[6]. For LMICs testing and the logistics of timeliness of access to the drug (within the 5 days therapeutic time window) will be the challenge compounding the prioritisation of access to medication
References
[1] Najjar-Debbiny R., Gronich N., Weber G et al. Effectiveness of Paxlovid in reducing severe coronavirus disease 2019 and mortality in high-risk patients. Clinical Infectious diseases https://doi.org/10.1093/cid/ciac443
[2] Dal-Re R., Becker SL., Bottieau E., Holm S. Availability of oral antivirals against SARS-C0V-2 infection and the rquirement for an ethical prescribing approach. Lancet Infect Dis 2022 ;22:e231-e238
[3] Katella K. 13 things to know about paxlovid, the latest COVID-19 pill. https:www.yalemedicine.org/news/13-things-to-know-paxlovid-covid-19
[4][ NHS (www.nhs.uk). About paxlovid. https://www.nhs.uk/medicines/paxlovid/about-paxlovid/
[5] GOV.UK. Highest risk patients eligible for new COVID-19 treatments: a guide for patients. Department of Health and Social Care
[6] Lei Ravelo J. A new consortium plans to get paxlovid to LMICs. https://www.devex.com/news/a-new-consortium-plans-to-get-paxlovid-to-lmi...
Competing interests: No competing interests
Dear Editor,
The reduction in the number of patients vaccinated with the AstraZeneca vaccine must, at least in part, be attributable to the fact that the vaccine efficacy (VE) of AstraZeneca falls far short of the high levels of VE obtained with the Pfizer and Moderna vaccines, respectively [1-8], and also attributable to the fact that prevalence of side effects such as the vaccine-induced thrombosis and thrombocytopenia syndrome [9], and transverse myelitis [10], are more prevalent in recipients of the AstraZeneca vaccine than in recipients of either of the two mRNA-based vaccines [10].
In the phase 3 trial which launched the AstraZeneca vaccine only 8,895 subjects received the 2 full doses subsequently deployed in the vaccination campaign. Vaccine efficacy in that study amounted to 62.1% (95% Confidence Interval 41% to 75.7% )[1], although a claim was subsequently made that increasing the dosing interval to 12 weeks had increased VE to 82.4% [2]. That claim, arguably, was based on a post hoc analysis which might, unknowingly, have included vaccination of subjects with previous SARS-2CoV-2 infection [3]. It is now recognised that, in previously infected subjects vaccination generates a higher antibody response than in previously uninfected individuals [4-5]. Accordingly, any evaluation of vaccine efficacy and dosing interval should take account of the confounding effect of previous COVID-19 infection.
A subsequent phase 3 study of the AstraZeneca vaccine (32,451 participants) generated a vaccine efficacy of 74% (95% CI, 65.3% to 80.5%) [6]. For the Pfizer vaccine (43,548 participants) VE amounted to 95% (CI 90.3% to 97.6%)[7]. For the Moderna vaccine (30,420 participants) , VE amounted to 94.1% (95% CI, 89.3% to 96.8%) [8].
Finally, in spite of the fact that the use of the AstraZeneca vaccine, both in France and in Germany, is far lower than in the United Kingdom, COVID-19 mortality in those two countries compares favourably with COVID-19 -related mortality in the UK [11].
References
1. Voysey M., Clemens SAC., Madhi S et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (ADZ1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021;397:99-111
2. Mahase E. Where are we on vaccines and variants. BMJ 2021;372:n597
3. 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. Lancet 2021;397:881-891
4. Payne RP., Longet S., Austin JA et al. Immunogenicity od standard and extended dosing intervals of BNT 162b2 mRNA vaccine. CELL 2021;184:5699-5714
5. Steensels D., Pierlet N., Penders J., Mesotten D., Hwylen L. Comparison of SARS-CoV-2 antibody response following vaccination with BNT162b2 and mRNA1273
JAMA 2021;326:1533-1535
6. Falsey AR., Sobieszczyk ME., Hirsch I et al. Phase 3 safety and efficacy of AZD1222(ChAdOx1 nCoV-19) Covid-19 vaccine. NEJM 2021;DOI:10.1056/NEJMoa2105290
7. Polack FP., Thomas SJ., Kitchin N et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. NEJM 2020;383:2603-2615
8. Baden LR., El Sahly HM., Essink B et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. NEJM 2021;384:403-416
9. Li X., Burn E., Duarte-Salles T et al. Comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with different covid-19 vaccines: International network cohort study from five European countries and the US. BMJ 2022;379;e071594
10. GOV.UK. Coronavirus(COVID-19) vaccines adverse reactions. Coronavirus vaccine summary of Yellow Card reporting. Updated 7 October 2022
11. STATISTA 2022. Number of novel coronavirus (COVID-19) deaths world wide as of November 8 2022, by country and territory. https://www.statista.com/statistics/1093256/novel-coronavirus-2019ncov-d...
Competing interests: No competing interests
We must stop waiting for things to go wrong to find out why
Dear Editor
The piece on “AstraZenaca’s covid-19 (mis)adventure”(Dec 10-17, 2022), continues the long British tradition of waiting to analyse why things go wrong after they go wrong, instead of considering the options before the event.
Part of the reason for this is the failure to provide a forum for assessment of options in advance. For example, many were unhappy with Oxford’s decision, but could find no way to have their concerns considered. And I couldn’t understand AstraZeneca’s absurd decision to test efficacy with a lengthy standard clinical trial, which would waste money, time and lives, instead of using the effect of the vaccine in preventing clinical infection after exposure to the Covid virus, in twenty healthy volunteers aged 18-25, an effect obvious in just two weeks.
Selection of a narrow course of action, without full consideration of all the possibilities, was apparent throughout the Covid epidemic, and missed options, such as isolation of the susceptible with maintance of social and industrial activity, are now being reconsidered. If there is just one lesson we can learn for Covid, it is that a wide consideration of the options is better before the event than afterwards.
Competing interests: No competing interests