Covid-19: What do we know about the late stage vaccine candidates?BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4576 (Published 24 November 2020) Cite this as: BMJ 2020;371:m4576
All rapid responses
The Royal Pharmaceutical Society guidance on the safe and secure handling of medicines recommends that to minimise manipulation of medicines in clinical areas injectable medicines should be in prefilled syringes (PFS) wherever possible . All media photos of the vaccines show 5ml glass vials but will they be distributed in PFS?
Having the vaccines already in PFS, certainly the ones that don’t require super low temperatures, would greatly improve the mass vaccination process. By not having to prepare the injection on the front line fewer skills and less training will be required and the process speeded up, probably reducing patient vaccinator contact time. PFS will make the process more sterile. Some of the side-effects such as redness and soreness at the injection site may be due to inadvertent contamination during the normal syringe preparation process, reported as high as 6% . Similarly any possibility of viral hepatitis transmission from using multidose vaccine vials and detachable needles will be completely eliminated. If the vaccines are put directly into PFS this would also stop the production of 14 billion unnecessary glass vials, which is more than the annual global production of injectable medicines and avoid the environmental consequences of their disposal.
Dr David K Whitaker FRCA
Chair Patient Safety Committee
European Board of Anaesthesiology
1 Royal Pharmaceutical Society. Professional guidance on the safe and secure handling of medicines. 2019. https://www.rpharms.com/recognition/setting-professional-standards/safe-...
2 Gargiulo DA, Mitchell SJ, Sheridan J, Short TG, Swift S, Torrie J, et al. Microbiological Contamination of Drugs during Their Administration for Anesthesia in the Operating Room. Anesthesiology. 2016;124(4):785-94.
Competing interests: Chair of European Board of Anaesthesiology (EBA) Patient Safety Committee. Member ESAIC Patient Safety and Quality Committee. Past member World Federation of Societies of Anaesthesiologists (WFSA) Safety Committee. Invited lecture fees from Aguettant Ltd and Medtronic - all paid to charity Lifebox. Provide consulting services to BD. Note: I have promoted the concept of prefilled syringes for over 20 years, BD make empty syringes and my agreement with them started 2 months ago.
Elisabeth Mahase summarises current knowledge on three leading covid-19 vaccines (1), much of which was made available via press-release. Given the hopes being placed on these vaccines for allowing a return to normality, it is important that results of these trials are released transparently and as quickly as possible. To help public health professionals preparing for vaccination programmes and clinicians, we have summarised and synthesised findings from the vaccines discussed in Mahase’s recent article (1) and seven additional vaccines with published phase II results, available as a preprint (2).
Across these 10 phase II trials, 3983 participants were included, with most trials recruiting those aged between 18 and 55-60 years. The mean or median age of participants across the trials ranged from 26.4 to 43.5 years. No participants under 18 years of age were recruited, and few over 80 years were.
All vaccines produced neutralising antibodies and T-cell responses, the latter not always measured. Side effects were mostly mild or moderate but included fatigue, localised pain, muscle ache and fever, i.e. symptoms mimicking mild covid-19 infection. Laboratory adverse events were reported. These included transient and mild neutropenia in 46% of a subgroup of 54 participants in the Astra Zeneca (Oxford) trial (2). One serious adverse event judged to be vaccine-associated was reported (fever requiring overnight hospitalisation (3)). Other serious side effects have been reported in the media or on websites from ongoing phase III trials.
Our summary and synthesis of published phase II covid-19 vaccine trials can provide insights for interpreting phase III trial results when they become available and for planning vaccination strategies. They may also help inform clinicians and facilitate patient education and communication.
1. Mahase E. Covid-19: What do we know about the late stage vaccine candidates?. BMJ 2020;371:m4576
2. Bhopal, Sunil and Olabi, Bayanne and Bhopal, Raj, Nature Of, Immune Reaction and Side Effects of COVID-19 Vaccines: Synthesis of Information from Ten Phase II Trials for Planning Vaccination Programmes (November 18, 2020). SSRN 2020. Available: http://dx.doi.org/10.2139/ssrn.3732847
3. Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. The Lancet 2020;396(10249):467-78.
4. Sadoff J, Le Gars M, Shukarev G, et al. Safety and immunogenicity of the Ad26. COV2. S COVID-19 vaccine candidate: interim results of a phase 1/2a, double-blind, randomized, placebo-controlled trial. medRxiv 2020. Available: https://doi.org/10.1101/2020.09.23.20199604
Competing interests: No competing interests
Interim results from Phase III trials of the vaccine developed by the University of Oxford and AstraZeneca were announced through media releases on 23 November. Much has been made of an apparent difference in efficacy between the intended regimen (two full doses of the vaccine) and another regimen (a half dose followed by a full dose). Whereas the efficacy in people given the planned combination was found to be 62%, that in the second group was 90%. Immunologists have suggested possible mechanisms to explain why starting with a reduced dose might be more effective. Their post hoc theories have fuelled hopes that 90% effectiveness could be achieved in vaccination programmes.
There has been far too little acknowledgement that chance is the most likely explanation for the different results between the two groups. In clinical studies, subgroup analyses must always be treated with caution – especially when there was no prior hypothesis that an intervention would be more effective in one subgroup. About a quarter of the vaccinated participants received an initial lower dose of vaccine because of an error in preparation, not because anyone suggested that this regimen would be superior. From the numbers released, it is clear that the difference in results between the two groups could easily have occurred by chance (and would not meet the conventional criteria for statistical significance). It is also concerning that the two groups appeared to have different age distributions, as well as different distributions across the participating countries.
The notion that a serendipitous error might have led to discovery of a more effective regimen is appealing. Unless there is further evidence from clinical trials, however, it would be wise to assume that the only reliable estimate of efficacy comes from the full data set – that is, 70%.
Competing interests: No competing interests
The Covid-19 epidemic has caused huge disruption of NHS elective surgery with consequential long delays for patients as resources have been redeployed to deal with the pandemic (1). In addition, major surgery is associated with post operative immunosupression potentially rendering patients vulnerable to the effects of Covid-19 infection postoperatively (2,3,4). The recent arrival of effective vaccines for Covid-19 is likely to have a pivotal effect upon the resumption of surgery. Policy makers who are currently considering a staged role out of the vaccine should consider the potential benefits of pre-operatively vaccinating patients such as those undergoing arthroplasty surgery. These patients are relatively small in number but pre-operative vaccination would allow us to proceed with their surgery with confidence.
Jonathan Prydderch Davies MB BCh FRCS FRCS(Orth)
Consultant Orthopaedic Surgeon
1. The Building Backlog of NHS Elective Cases post Covid-19. Macdonald N et Al. BJS Volume 8 Issue 6 P544-546 June 01 2020
2. Surgery induced Immunosuppression. The Surgeon. Hogan B V et Al. Volume 9 Issue < Feb 2011 Pages 38 – 43.
3. The influence of surgical stress on the psychoneuro-endocrine-immune axis. Dahanukar SA,et Al. J Postgrad Med. 1996 Jan-Mar;42(1):12-4.PMID: 9715290
4 Immunologic Consequences of Surgery, Anaesthesia and Blood Transfusion. Surgical Immunosuppression. Nielson H J et Al. Ugeskr Laeger. 1989 Sep 11;151(37): 2348-52. PMID:267647 Review.
Competing interests: No competing interests