At the iConnections Investment Institute Fall Forum, we heard from Dr. Gregory A. Poland, M.D., Director of the Vaccine Research Group at the Mayo Clinic. In his fascinating talk, Dr Poland gave us an update into the progress that has been made into a vaccine for COVID-19, and made some predictions about what we will face in the year ahead.
Adenovirus vaccines in development
The adenovirus vaccines are based on common cold viruses. For AstraZeneca’s vaccine it is a chimpanzee adenovirus. This study had been on hold in the US for 6 weeks as the result of an adverse event in the clinical trials, but has now resumed. Johnson & Johnson has a human adenovirus virus vaccine that will either require one or two doses — this study had also been paused in the US but has resumed. Both Russian and Chinese laboratories are working on their own adenovirus-vectored vaccines, but I can tell you that these will not be available in the USA.
RNA vaccines in development
Let’s look at the mRNA vaccine. This is based on a portion of the SARS-CoV-2 genetic material. Two of them are being tested: one by Pfizer, and one by Moderna. Both have full-length S proteins, both have been reactogenic. The major issue is that both require cold or ultra-cold storage. Moderna’s vaccine needs to be stored at -20 C, and the Pfizer at -80 C. It’s a big issue, particularly outside the US, but even inside the US most medical institutions cannot store large quantities of a vaccine like this.
Novavax is developing a recombinant S protein vaccine. This requires two doses, at day 0 and day 21. They found antibody titers up to four times those seen in normal human convalescent patients. This is now going into a phase 3 trial in the UK, and will soon have a phase 3 trial in the USA with 30,000 subjects.
A summary of the current vaccines
There is no clear winner yet, no efficacy or durability data yet. We have insufficient safety data. The good news is that all, or nearly all, subjects in these studies developed what we think will be protective antibodies and T-cell responses that were similar to or exceeded convalescent human plasma. All of the vaccines protected non-human primates, that is to say, monkeys, who got the vaccine and then were given the wild virus and did not get sick.
Most of the phase 3 trials will only have 20,000 subjects, which is not many for a novel vaccine that has not been tried in a meaningful way before. With this size study, it is powered to detect a significant or serious adverse event occurring at a rate of 1 in 5000 people. To put that in context, many people in America are afraid to get the influenza vaccine because of a one in a million chance of getting Guillain–Barré syndrome, so we will have to be aware of people being resistant to receiving COVID vaccines.
So let’s look at the numbers. There are 350 million people in the USA. Of those, 122 million are high risk people who need the vaccine first. Globally, we have 7 billion people. And it’s likely to require two doses to achieve protective immunity — that’s 14 billion doses. This has never been done before. We don’t even have the glass vials to get this done. How do we create this global production capacity?
The question then becomes one of who gets it, and when. In the US, this will begin with critical healthcare and other workers, some 12 million people. Then the other healthcare workers and essential workers, and high risk populations — around 110 million. After that comes the 206 million general population. When will that be? Well, that depends on when it can be manufactured, and what the supply chain looks like.
However, I have 90-95% confidence that the population in the US will have access to a vaccine by the second-third quarter of 2021.
Mutations and evading vaccines
This virus is an RNA virus. It can change characteristics, that is, mutate — in fact, it already has. So, could this virus evade our vaccine and immune responses like influenza does year on year? The answer is yes. A Rockefeller study put the SARS-CoV-2 virus through human cells multiple times: it mutated, and acquired mutations that allowed the virus to evade monoclonal antibodies and COVID convalescent plasma.
As the news has already reported, we know that the virus already mutated in its spread across the US. Almost immediately after reaching the US, the virus mutated, and now this mutated version is the main one. There’s nothing to stop it mutating into something more or less lethal or even the same level of lethality. But could it mutate to evade the developing therapeutics and vaccines? The real answer is, no one knows.
What we don’t know yet
What is the efficacy of vaccines when masks are off? Right now, we are running trials where people are wearing masks and taking protection measures. When there is no protection, what will the rate be? And is the vaccine going to be safe for children, or pregnant women? How long will the vaccine protect us for, and will vaccines be interchangeable?
I think we will continue doing what we are doing now for some time, unless vaccines turn out to be very efficacious, and people take them at high rates within the population. That means mask wearing, hand washing and social distancing has to continue, even after vaccination. There is a risk for a twindemic to occur: when flu and COVID-19 are both in the population, and we may need to consider the effect of other SARS-CoV-2 mutations.
In the UK, they are considering a controlled human challenge trial. This would mean immunizing people with an experimental vaccine and then deliberately exposing them to the virus. The advantage is you get fast results. The disadvantage is that you don’t yet have rescue therapies that are totally effective.
We have seen denial, fear and ignorance, and overpromising in regard to this pandemic. An inability to formulate common international protocols, so we are reinventing the wheel with each new emerging pathogen. Research and preparedness funding only lasts as long as the human attention span. This is the third novel coronavirus to jump to humans since 2003. It’s shocking that we are so far behind with dealing with this.
A note of caution: there is immense pressure for treatment and vaccines – but there’s no substitute for careful clinical studies and trials. We cannot do ‘science by press release’ and must remember that the plural of anecdotes is not data. The Hippocratic oath still applies: first, do no harm.
This leads to tensions. There is an irresolvable tension between speed and safety. The efficacy of a vaccine is generally easily determined, but safety is significantly harder to gauge. You have to check it is safe over time, that it works in different subpopulations, and with concomitant vaccines and medical conditions.
Anticipations for Fall and Winter
A long and deadly winter is highly likely. We are likely to experience a concurrent influenza epidemic alongside the coronavirus pandemic. While the southern hemisphere saw almost no flu in their winter season, remember that they are generally mask-wearing societies. In the US we also face concurrently negative synergistic events. That includes a contentious election, natural disasters, recession and disruptive cultural issues.
Humans tend towards what we call the complacency-crisis-complacency cycle. It begins with denial, then moves through stages of recognition, panic, fleeing, hoarding, miracle cures, blame, acceptance, responses, and finally, recovery.