A physician on 9 issues that would go unsuitable with the brand new vaccines

Think about the performance. Within a month of the appearance of SARS-CoV-2 – the coronavirus that causes Covid-19 – its genome was sequenced. Three months later, the first vaccine candidates in clinical trials were injected into human volunteers.

Now, less than 12 months after the first case was identified in Wuhan, China, the US is set to launch the largest mass vaccination program in its history. Few advances in modern science can match the speed and audacity of the coronavirus vaccination program. With the upcoming emergency approval of the Pfizer / BioNTech vaccine by the U.S. Food and Drug Administration, the long obscurity of the pandemic, which killed more than 283,000 Americans and more than 1.5 million people worldwide, seems soon to be relegated to the litany Global tragedies will be a thing of the past.

As a doctor, clinical researcher, and epidemiologist, I'm excited about the vaccine data to date. The 95 percent effectiveness of Pfizer / BioNTech and Moderna mRNA vaccines is unprecedented and better than any of us hoped.

But we have to be careful. We need to temper our excitement by realizing that the vaccine is a weapon we may not be fully prepared for.

A lot can still go wrong.

I'm not interpreting my worries here as a damp blanket, but because I am worried. And, like all warriors out there, one of the reasons I worry is to make sure the things I worry about don't actually happen.

By worrying together, we can prevent a lot of this from happening. I offer my worries in a convenient list format, with low to high probability.

1) Unexpected long-term side effects (probability: low)

Although mRNA vaccines have never been used in a large-scale vaccination trial, theoretically not a ton can go wrong here.

The mRNA molecule is incredibly unstable – it is so easy to break down that it has to be transported in extremely cold conditions. It cannot be integrated into DNA, so there is no risk of human-coronavirus science fiction mutants emerging. Some scientists have raised concerns that an immune response to RNA could later lead to some autoimmune diseases (like lupus), but extensive testing in humans has not yet shown this.

2) There won't be enough vaccine for everyone (probability: low)

We're probably in good shape here if we define the vaccine as "the stuff that goes in a vial and eventually your arm". One of the main advantages of mRNA vaccines is that they are pretty easy to scale. In fact, you can make about 1 million cans in a bioreactor the size of a Cola bottle.

We don't just have to rely on the mRNA vaccines, however. AstraZeneca's vaccine (which contains a bit of coronavirus genetic material wrapped in adenovirus sleeve) has seen some setbacks lately, but is likely to join the fight in the next few months. Johnson & Johnson's vaccine – known as a single-dose vaccine – could get emergency approval in early 2021.

And the pipeline is full: there are currently 13 vaccines in Phase 3 trials (excluding the Pfizer / BioNTech vaccine), 17 in Phase 2, and a number of other vaccines that are still in the early stages of testing. Many of these vaccine candidates target the coronavirus spike protein – the same target that has resulted in high efficacy rates among the front runners. If these attempts can quickly recruit participants, our tools will increase dramatically.

There is one problem, however: the presence of effective vaccines (like Pfizer / BioNTech and Moderna) can dampen recruitment in ongoing trials. If you're in a study, you usually have a 50 percent chance of getting a placebo instead of a vaccine. Will individuals continue to volunteer when an effective vaccine may be on the market soon? We'll know soon enough.

3) The vaccination is politicized (probability: low)

Am I also Pollyannaish in this case? I can't imagine Republicans desperate to reopen society at all costs would look the vaccination gift horse in the mouth. Even so, the current leader of the Republican Party was a "vaccine skeptic".

However, the vaccine could prove to be the most widespread achievement of Donald Trump's presidency. And I encourage him to gain recognition – his ranting about the vaccine can increase vaccination rates among his followers, many of whom are increasingly skeptical of science and have "low social confidence."

4) There won't be enough vaccine (probability: medium)

This is more of a problem. Vaccines require glass vials, needles, alcohol swabs, and – in the case of the Pfizer / BioNTech vaccine – a staggering amount of dry ice. Pfizer actually cut its vaccine delivery estimates in half due to unspecified shortages in these products. These products are generally not made by the vaccine manufacturer and must be obtained from other companies.

Despite Operation Warp Speed's success in accelerating vaccine development, the federal government has defied calls to enact the Defense Production Act to increase the supply of these critical components of the vaccine program.

So we have the option of having plenty of vaccines in the freezers, but not enough needles to get them into enough arms. This would slow the introduction of the vaccine and prolong the pandemic despite approved vaccine candidates.

5) people don't get both doses (probability: medium)

Multi-dose vaccines are nothing new – measles, mumps, rubella (MMR), rotavirus, and tetanus are multi-dose vaccines. But these are routine vaccines for kids, and parents are a little more obsessed with their children's health than they are with their own.

Parallels to the seasonal flu vaccine don't help either. Getting an annual flu shot is easy because it's only one. And to be honest, we're not even that good at getting our annual flu vaccine (only 45 percent of adults in the US got their flu vaccine during the 2018-2019 flu season).

How many of us will remember returning three weeks later for the booster Covid-19 shot? This has some real ramifications. First, people may feel protected if they don't. This leads to behaviors (crowded post-vaccination dinner parties?) That spread the virus even faster.

But there is a bigger problem here. Several virologists have suggested that inadequate vaccinations could allow the virus to develop "vaccine resistance". The idea here is that a partially vaccinated person can get a low-level infection and the selection pressures within that person favor viruses that can evade the immune response induced by the vaccine.

I asked Yale immunologist Akiko Iwasaki about the possibility, "It is conceivable that people who only have one shot of the vaccine could become infected, resulting in an escape mutant," she said. "This is purely hypothetical at this point, as we have not yet seen such escape mutants come from naturally infected people with suboptimal immunity."

So what are we doing to get people their second shot? Here are some ideas from Dylan Scott at Vox.

6) Doctors Will Bend The Truth To Help Their Patients Get A Vaccine Faster (Probability: Medium)

Until vaccines are ubiquitous, we need to prioritize who gets them first and who has to wait. The Centers for Disease Control and Prevention has published their first guidelines, which will focus on healthcare workers and residents of long-term care facilities in the first phase of the rollout.

In phase 2 it will be difficult. We don't have much clarity yet, but it is likely that the vaccine will be reserved for people with pre-existing medical conditions (such as old age, diabetes, and possibly even obesity). How does your local CVS know you have these comorbidities? Your doctor will most likely have to vouch for you.

This creates some perverse incentives for doctors like me, who often think more about the benefits for individual patients than for society as a whole. Should I double check my blood pressure to see if I can make a diagnosis of hypertension? Should I check the obesity mark on the vaccine form even if the patient is just overweight? And lest you believe doctors are immune to this type of behavior, let me remind you how often we give antibiotics to our patients for no good reason – 30 percent in the largest study to date.

We want to make our patients happy. That is not always the right thing to do. There is certainly a problem with injustice, but the bigger problem with doctors who rate people at "high risk" is inappropriately allocating scarce vaccine resources to those who would probably be fine without them. While vaccines are scarce, it is important that we vaccinate the actual highest risk groups, not the people doctors may consider high risk.

7) Vaccines exacerbate health inequality (probability: high)

This is really an episode of # 3, but something that keeps me up at night. There are currently 80 million people in the United States without regular access to medical care, many of whom have significant comorbidities that no one has documented. These are predominantly colored people with a lower socio-economic status. These are also the people who suffered the most during the Covid-19 pandemic.

In other words, they are the people who would benefit the most from the vaccine. And they can be left behind.

To prevent this from happening, we need targeted vaccination programs in low-income and underserved communities. We must also do away with comorbidity restrictions for those who do not have access to quality health care. California's proposal to incorporate "historical injustice" into vaccine allocation is not far from the goal.

8) A false sense of security arises (probability: high)

Ninety-five percent effectiveness is nothing to sneeze at. Even if people loosen up, go to dinner, and wear fewer masks after being vaccinated, with this effectiveness we should still see a dramatic decrease in infections.

The problem with the false sense of security is not social, but individual. If a vaccine is 95 percent effective, anyone who receives it will assume it is 95 percent effective. Nobody thinks they are in the 5 percent, but 5 out of 100 people are. If these five people stop engaging in social distancing and wearing masks before the end of the pandemic, they may still suffer from the most serious consequences of Covid-19.

9) Anti-Vaxxer amplify and misrepresent side effects (probability: almost certain)

It's already happening. The real concern is how much this will affect the overall vaccination effort. We need to vaccinate (or infect with Covid-19, which would be ethically wrong) around 70 percent of the population for herd immunity to end the pandemic. That's a high bar, and social media's ability to reinforce and spread false or misinterpreted news far and wide is enormous. I'm not worried about the "microchip tracking devices" nonsense. I worry about anecdotes.

I remember a story Paul Offit, a vaccines expert at the University of Pennsylvania and a member of the FDA Vaccine Advisory Board, once told me while I was at the residence. He was about to vaccinate a child with the MMR vaccine. Five minutes before the vaccination, the child had the first seizure of his life. Can you imagine what would have happened if this seizure had occurred five minutes after the vaccination?

We will vaccinate hundreds of millions of people. Someone is going to have a seizure after receiving the vaccine. Someone is going to have a heart attack. Someone is going to get in a car accident and someone is going to die by suicide. These stories will burn like wildfire through social media. And remember, anecdote and evidence are not the same thing.

Are there any other worries? Absolutely. What is causing the whole effort to fail may be something neither of us has thought of. It will be important to stay flexible, stay optimistic, face the challenges ahead and keep hope alive so that we can keep each other alive.

F. Perry Wilson, MD MSCE, is an Associate Professor of Medicine at the Yale School of Medicine and Director of Yale Accelerator for clinical and translational research. He writes over a weekly column and is the creator of the free online course "Understanding Medical Research: Your Facebook Friend Is Wrong."

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