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What if we could get a shot, well actually two shots at the same time, that could protect us from contracting COVID-19 for six months or longer?
What if this was independent of our ability to form antibodies, independent of our T cells being in tiptop shape, independent of having a fully competent immune system?
That is the promise of the PROVENT trial, a Phase III Double-Blind, Placebo-Controlled Study of AZD7442 for Pre-exposure Prophylaxis of COVID-19 in Adults.
The study is using a passive immunity approach in the hopes of helping those who are less likely to benefit from vaccinations due to being immunocompromised.
For the background on passive versus active immunity, please see my post here.
AZD7442 is a mix of two long-acting neutralizing antibodies directed against the spike protein of the SARS-CoV-2 that were chosen for their potency from the plasma of patients that had successfully recovered from COVID-19. They were then cloned to produce a mix of two monoclonal antibodies or mAbs.
CLL patients are already familiar with mAbs such as rituximab or obinutuzumab that attack CD20, a surface marker found on all B cells, including CLL cells.
Instead of targeting cancer cells, these antibodies are directed at epitopes or parts of the spike protein of the virus that causes COVID-19.
The hope is that this long-acting cloned antibody response will bind to any spikes should the SARS-CoV-2 try to gain entry into a patient who has received the experimental mAb, thus preventing it from infecting the cells and sickening the patient.
The antibodies have a half-life of approximately three months, so if they work as promised, the pharmacokinetic suggest that protection should last at least 6 months and maybe nine or twelve months.
As discussed in my prior post on passive versus active immunity, this approach largely abrogates the need for CLL patients to launch an immune response on their own. Chronic lymphocytic leukemia is a cancer of the immune system. We know that our ability to respond to new vaccines is unpredictable at best and we have no data yet on how protective the SARS-CoV-2 vaccines will be. CLL patients have been documented to have diminished numbers and functionality of normal B cells that are needed to form antibodies and have T cells that act as if they are “exhausted.”
This immunocompromised state contributes to our poorer prognosis with COVID-19 and to our concerns that vaccines may not be as effective compared to those with an intact immune system.
So, this passive approach makes sense.
What are the trial details?
The trial is open and recruiting in several countries and several sites across the USA.
From the PROVENT website:
“The study is now enrolling volunteers who have an increased risk of getting COVID-19 due to location, employment, or personal circumstances. You may also be interested in the study if you are less likely than most adults to benefit from a vaccine. For example, due to older age, obesity, or immunosuppression from a health condition or medication.”
That last sentence is talking to all CLL patients.
The trial works like this.
If you qualify, and you will be screened first and checked that you don’t have an active COVID-19 infection by a nasal swab, then on a lengthy first visit after blood and urine specimens are collected, vitals checked, EKG and physical exam is completed, you drop your drawers and are randomized to be injected with 1.5 mL in each cheek of either AZD7442 or a placebo. Two out of three get the active drug, but you won’t know and neither does the clinic. That’s what makes it a double-blinded randomized control trial, the gold standard of medical research.
You have several much shorter follow-up visits over the next year. The primary endpoint they are looking for is the incidence of the first case of SARS CoV-2 positive symptomatic illness over the next six months, though they also look at twelve months and a whole bunch of other secondary outcomes.
Sounds good, but you may have a few questions
What if you’ve already been vaccinated?
You are excluded. Quoted from the exclusion criteria:
“Any prior receipt of investigational or licensed vaccine or other mAb/biologic indicated for the prevention of SARS-CoV-2 or COVID-19 or expected receipt during the period of study follow-up.”
So, you must make a choice, vaccine or antibody. I suspect the vaccines were authorized much sooner than those who designed this trial anticipated.
I argued with the researchers that they should open a cohort for already vaccinated patients who do not form antibodies post-vaccine. Aren’t those exactly the folks who most desperately need passive immunity?
Let’s say you have enrolled in the PROVENT trial, you received your shots, and are hoping you didn’t get the placebo but you don’t know. Then your doctor calls and says, “Good news! I have a vaccination slot open for you next week.”
What to do? The trial has been amended to allow you to stay in post-vaccine. It also allows you to be unblinded (it can take a few days) to see whether you received the active mAb or the inert placebo.
Once unblinded, you can make an informed decision. The researchers will not advise you as to what to do, but I would suspect nearly all those who learn they were randomized to the placebo would want to be vaccinated, and now they can stay in the trial.
If you received the active antibodies, there is good reason to believe that it might blunt or in some way alter your response to the vaccine, though this is just speculation. More importantly, if the mAbs work as promised, you may already be protected without the vaccine. The decision is only yours to make, but either way, you are asked to complete the trial.
I do not want my choice to unduly influence your decision, so I will only disclose that I am a big believer in this mAb approach for CLL patients like myself and I did enroll in the trial. I was randomized and got the two shots on January 12, 2021. I have had no ill effects from the injections. And so far, nothing that hints at a COVID-19 infection, though I am still very much locked down so my exposure risk remains low. I am very cautious and very fearful of COVID.
I want this trial to succeed, though I recognize as more and more of us get vaccinated, it will be harder to get good data. The passive immunity it offers will be more expensive and probably less durable than the active immunity conferred by vaccination, but it is also likely to be more predictable for CLL patients.
If it means shots every six months, so be it, sign me up. But first, we have to get it approved.
For more on the trial details, read its description on clinicaltrials.gov.
The trial website is helpful and can be accessed here.
We know that the two authorized anti-spike protein mAbs mixtures help COVID-19 patients when given soon after diagnosis.
Using similar but longer-acting antibodies pre-exposure seems like a smart strategy, let’s see if it works.
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer