Regeneron have published a press release today reporting positive interim data from their Phase 3 clinical trial evaluating the use of REGEN-COV™ antibody cocktail as a passive vaccine for the prevention of COVID-19 in people at high risk of infection.
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“This is a different type of medicine for Covid than others that have been tested in trials. It is called a “Passive vaccine” because it is used for prevention of Covid disease but given to people before they are exposed to the virus, just like an ordinary vaccine. An ordinary vaccine is given to “train” the body’s own immune system to mount a defence against the infecting virus. The body’s immune system then produces antibodies and other defences to provide the defence. Here instead of requiring the immune system to provide antibodies, it involves injecting antibodies directly to someone and does not rely on their own immune system alone to respond.
“With REGEN-COV, there are two antibodies that have been based on antibodies from patients who recovered from Covid. It is more like the use of convalescent plasma, but is not intended for treatment of Covid in this interim trial report, but for prevention of infections where a household member had tested positive and is given by injection.
“According to clinicaltrials.gov it is intended to recruit 2450 patients in total (though this includes some who have Covid and so the medicine in that case is evaluated as a treatment rather than for prevention).
“This interim result (which would not normally, i.e. non-pandemic) be reported, is based on about 400 patients. It shows that both symptomatic and asymptomatic infections were prevented. The evidence on hospitalisations and deaths is far too limited to draw strong conclusions.
“As a prevention of Covid disease it would probably be too expensive for very widespread use (we are not informed of its cost), but it could be very useful in situations where people are at very high risk of exposure to the virus and their own immune system is deficient in its response to any standard Covid vaccine.
“The trial is conducted in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) and is likely to be very well conducted and monitored.”
Dr Peter English, Consultant in Communicable Disease Control, Former Editor of Vaccines in Practice Magazine, Immediate past Chair of the BMA Public Health Medicine Committee, said:
“The natural history of Covid-19 comprises several phases – a period from infection to the onset of symptoms (if there are any symptoms – the proportion of asymptomatic cases seems to depend in part on how hard you look for symptoms, and is higher at younger ages). Infectiousness appears to start up to 48 hours before the onset of symptoms, and ceases by about 8 days after the onset of symptoms. Those who have symptoms in the early stages of disease generally have flu-like symptoms. Roughly 10 days from the onset of symptoms some people start to develop more serious complications, which appear to be due to an over-reaction of the immune system. By this stage, the [viable, potentially infective, “active”) virus has usually been mostly or completely cleared, so disease progression from this point probably doesn’t require the ongoing presence of virus. For this reason, it is unclear what the value, at this point in the disease, of antibodies to the virus might be.
“If antibodies to the SARS-CoV-2 may be effective as treatments, it would be very early in the course of the disease, ideally before infection.
“The difference between vaccination and the use of these monoclonal antibodies, is that vaccines stimulate the body’s immune system to produce its own antibodies – and, indeed (if the vaccine works this way) to produce a broader immune response, including T-cells and so on. By contrast, monoclonal antibodies such as those in REGENERON’s product, or Bamlanivimab, do not involve any of the body’s own immune response to the pathogen, and will have only a temporary effect.
“These interim results describe how either REGENERON’s REGEN-COV monoclonal antibody cocktail or a placebo was given to 409 “at risk” individuals who were exposed to Covid-19 in the household. This is a group who are both at high risk of infection (through the household contact), and at high risk of an adverse outcome, having at least one of a list of well-recognised risk factors.
“REGERON describes this – perfectly reasonably – as “passive vaccination”. They report that none of the product’s recipients (0/186) compared to 8/223 placebo recipients had symptomatic infection (it’s not clear how hard they looked for symptoms, but I would assume that they would not have missed more serious disease requiring hospital admission); and that asymptomatic infection was roughly half as common in those who received passive vaccination. (23/223 placebo vs. 10/186 REGEN-COV participants). They describe a number of other markers – duration of infection, viral load, duration of viral shedding – which were decreased in intervention patients.
“Given that monoclonal antibodies work in a similar, if temporary, way to vaccines, perhaps trials of such products should be compared to those for vaccines. Vaccine trials are usually very large: the Moderna trial1 had 30,420 participants; the Astra-Zeneca trial2 enrolled 23,848 participants and extended to 74,341 person-months of safety follow-up; and the Pfizer-BioNtech trials3 enrolled 43,548 participants. This is partly because the ethics of giving a preventive treatment like vaccination are very different from giving a treatment for a disease. When somebody is ill, especially if the prognosis is poor, they may accept treatment with a poorer probability of success and a worse adverse event profile than when you offer a preventive treatment to somebody who is well. So, with vaccines, it is very important to detect even quite rare adverse events; and to be fairly confident about their efficacy.
“As a preventive treatment you might expect the same to apply to REGENERON’s product; but these preliminary data are based on 409 participants, and the overall phase III trial, with (presumably) fewer than 3000 participants, is small compared to vaccine trials.
“However, given the risks to those enrolled, a poorer risk-benefit equation (and cost-benefit ratio) may be acceptable in such populations
“These initial results are encouraging, suggesting that the product may have efficacy against both symptomatic infection, and any infection (and therefore onward transmission) of SARS-CoV-2.
“It remains a small trial, but there may be a place for it as e.g. post-exposure prophylaxis in people at particularly high risk of Covid-19.
“Whether it will be cost-effective is not clear at this stage.”
1. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 2020. (https://www.nejm.org/doi/full/10.1056/NEJMoa2035389).
2. Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK, 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. Lancet 2020. (https://doi.org/10.1016/S0140-6736(20)32661-1 or https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32661-1/fulltext).
3. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 2020;383(27):2603-2615. (https://www.nejm.org/doi/full/10.1056/NEJMoa2034577).
Dr Penny Ward, Visiting Professor in Pharmaceutical Medicine at King’s College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:
Is this good news?
“This is preliminary data from a post exposure prophylaxis (prevention) trial using a subcutanous or intramuscular injectable form of a mixture of two anti SARS CoV2 antibodies produced by Regeneron. The design of the trial matches similar studies conducted previously for influenza antiviral medications. To be eligible for the trial, subjects had to be resident in a household in which at least one other member had tested positive for/had symptoms of COVID in the preceding 4 days (96 hours). As anticipated, given the already proven antiviral efficacy of this antibody mixture when given intravenously to individuals with COVID in hospital, receipt of the antibody – which inhibits spread of the virus in the body – limited productive infection and completely prevented symptomatic disease in recipients.
Is the data convincing or do we need more to be sure?
“The trial is ongoing and is expected to generate further, confirmatory data as it progresses over the next few months.
Is there enough data available in this press release to be able to assess the results?
“The information including details of the treatment given and the comparison of baseline characteristics between the treated and untreated contacts should be published as rapidly as possible, as the details provided in the press release do not fully enable scientific assessment, but the topline information is interesting enough to suggest that this may offer additional options for management of COVID pending completion of the vaccination campaign. We also need to see information on any escape mutations noted in treated individuals.
What do the data suggest?
“Taken together with the already available treatment information showing antiviral effect when given early in the disease course, this suggests a potential avenue for early intervention in outbreaks of disease and to prevent infection and illness in an institutional outbreak for example in a university, prison, care home, hospital or essential workplace (e.g. food factories, PPE production units).
Are there any implications?
“Vaccination will prevent disease but takes 14-21 days to take effect: in an immediate contact situation, this is too long to prevent illness which may, in an individual at high risk, be fatal. This approach could protect patients receiving chemotherapy for cancer, enable control/prevention of outbreaks in an institutional setting and reduce pressure on health services.
Any other comments about this news/data?
“This was not unexpected but is a potentially exciting addition to the therapeutic armamentarium.”
All our previous output on this subject can be seen at this weblink:
Prof Stephen Evans: “No conflicts of interest. I am funded (one day per week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator on any grants obtained from them. I am the statistician to the ‘meta-Data Safety and Monitoring Board’ for CEPI. I am paid for my attendance at those meetings and will be paid expenses for travel if that occurs. I am a participant in the Oxford/Astra Zeneca trial, and on 13th January 2021 learnt I had received the active vaccine.”
Dr Peter English: “No DOI – nothing to declare.”
Dr Penny Ward: “No COIs. I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Until July 2019 I was Chief Medical Officer of Virion Biotherapeutics, which was a company developing broad spectrum RNA therapy for the treatment/prevention of respiratory virus infections. Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases. Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”