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Guest post by vaccine advocate Denise Kesler Olson. She currently works for an Immunization Coalition in Arizona, helping others feel as passionate about vaccines as she does. You can read how she got involved in the immunization movement here.  This information originally appeared on her Facebook wall, and she has graciously allowed me to post this edited version on my blog. I am re-editing it after we have more data in 2021 – Dr. Shaham

Part I: “But How Do We Know If It’s Safe!?”

The most common criticism I get is that I keep telling you how every vaccine is safe, and therefore I must unconditionally love all vaccines and accept them all blindly. No. I – and really, we’re talking about the scientific establishment I support and not me personally –accept only vaccines that have been through the rigorous testing process and are found to be safe and effective. The vaccines on our standard schedule have cleared that hurdle. Covid vaccines aren’t in that category yet. We do not know if they work nor if they are safe. I wouldn’t recommend everyone get them yet (November 2020), and no responsible organization should either (since they have not YET undergone independent scientific review). 

A little background information will go a long way to help us here. Vaccines are a special type of medical product because they are given to healthy people instead of sick people. This might seem like a small thing, but it’s actually a HUGE difference. Pharmaceuticals are only ethically given when the possible benefit outweighs the possible risk. If you are already sick, it may be worth risking side effects, especially when they rarely happen or if they are less serious than the problems you already have. A vaccine given to healthy people must never make them into really sick people, or the whole point of preventing illness is defeated! Any effects need to be better than the alternative of not getting the vaccine at all. 

Vaccines need to pass through four specific development phases to be proven safe and effective (preventing the disease). If any serious side effects are found throughout this process, the vaccine will not be approved for mass use – about 60% of vaccines fail to be approved in the end (compare this to 84% of other pharmaceuticals which fail). First, various vaccines that have worked in the laboratory setting, and look good on paper and computer modeling, are tested on animals to prove that the formulation isn’t harmful to live beings and see which candidates are the most promising. The vaccines that work safely and as expected in animals can then move forward to be tested in humans in phase I, II, and III clinical trials. Pediatric vaccines (the ones we use in kids) usually undergo phase IV clinical trials as well, which are formal studies that occur after the FDA approves a vaccine. Check out this infographic from the CDC about how a vaccine gets to market (click on the sentence to open the link in a new window) or click here for a short YouTube video about the process. 

There are currently Covid vaccines undergoing phase I, II, and III trials in adults all over the world. The phase III studies on people are double-blind. That means the participants are divided into groups, and half of the people are randomized to receive the real vaccine that is being tested, and half receive something else (a placebo), such as a saltwater injection or a different vaccine. Neither the patient nor the medical staff administering the vaccine knows if the real vaccine was given. Only the data analysts have this information, and it is kept separately from any information identifying people in the trials, such as their name, birthday, street address, or characteristics. This is important because not everything that happens to people after getting a shot will be because of the injection. People in both groups will get sick or injured by random chance -especially when following up with them for a long time. Scientists look for patterns. If one thing shows up repeatedly in the group of people who got vaccinated, then that may be a sign that the vaccine caused it.

This knowledge will help you understand scary headlines in the news. Recently, there were wide reports that someone in Brazil had died while participating in a vaccine trial. When the researchers paused the trial, they used emergency protocols to unblind his records.  It turned out that he was not given the real vaccine during the trial, so the vaccine they were testing could not be the cause of his death.

Obviously, you test vaccines not just to prove that they are safe but also to prove that they prevent people from getting sick. There are two ways that people can go about this. One way is to continue watching phase III trials (currently around 30,000 people or as many as they can get for vaccine trials) for a very long time until enough people are naturally exposed to the virus. Over time, you hope to see a pattern of people who were given the real vaccine not getting sick, hardly ever getting sick, or only getting mildly sick. If the vaccine does not work, then the people who got the real vaccine and the people who got the placebo will get sick roughly in the same amount and severity overall. Remember this when you hear numbers like “this vaccine is only 50% effective,” because it means people in the vaccinated group were half as likely to get ill with COVID-19 compared to the placebo group. While that would not be the best, it would be a huge reduction of disease overall.

The other way to see if vaccines work is controversial, but it did get approval for use in the UK recently in healthy and willing volunteers. This is the old-fashioned challenge trial. In a challenge trial, you give the vaccine and then deliberately try to infect those people with the disease you are trying to prevent. The advantage is knowing right away if people get sick in the same numbers and skipping months of waiting around for people to become exposed. Still, infecting people on purpose with a disease, when you do not know if you have a safe or effective vaccine, has many disadvantages and is considered unethical by many people. 

Part II: Operation Warp Speed

There are a couple of hurdles that keep vaccines from coming to the market quickly, even if the idea is good and it works. 1: There may not be enough money to continue research and development. In that case, work must be paused as researchers try to obtain new grants/investors/sources of funding. 2: It’s hard to scale up the production of an effective vaccine so that there are enough doses to immunize everyone in a large population. It costs quite a bit of money to build or retrofit a factory and obtain all of the necessary materials to make millions of doses of a new vaccine.

Operation Warp Speed was passed as part of the CARES act in March 2020 to speed up a successful Covid vaccine’s availability. Ten billion dollars went into funding a public-private partnership that gives R&D money to companies with candidate vaccines, as well as supplying funding to scale up factories to manufacture those vaccine candidates, even when we are not sure they will ever be approved. They did this with the knowledge that some of them would probably not be proven to be effective in the trials and would ultimately have to be tossed out, but that if one worked, then there would be millions of doses sitting ready to be shipped out as soon as final approval was given. The reasoning behind this effort was set out by top economists who supposed that a delay of even one year could cause much more economic damage and turmoil than simply funding the vaccines upfront and getting things back to normal.

Like everything that comes out of Congress, the law is very complicated and full of fine print. It leaves a lot of questions, such as:

• What loopholes could pharma companies exploit to inflate their stock prices?
• Should the American people have to pay for a vaccine funded by taxpayer dollars?
• Should we be awarding money to foreign companies under this program?
• Were contracts awarded fairly and subject to enough scrutiny?

And on and on and on. We will probably be talking about what went right and what went wrong with Operation Warp Speed for decades to come. However, that is an argument for somewhere else. I brought it up because I want to help everyone understand that Operation Warp Speed does not fundamentally change the clinical trial process I talked about before, where we check the safety and efficacy of vaccines. It has a dramatic name, but it should really be called “Operation Fund COVID Vaccines.” There are legitimate reasons to critique the operation, but they have nothing to do with the safety and effectiveness of the eventual vaccines produced. Questions about pharmaceutical companies, including how much money they should be allowed to make if they receive public funds, are economic and political questions at heart. The companies participating still have to prove that their vaccines are safe and work; otherwise, their whole tax-payer funded factory will just sit there gathering dust.

Addendum from Dr. Shaham: Operation Warp Speed is allowing manufacturers to reduce the typical 2-year long phase II clinical trials and 2-year long phase III clinical trials into an overlapping 6 month trial period before assessing the vaccine safety and efficacy, due to the urgency of getting a vaccine out to halt the pandemic, and a large number of people in the trials. However, this does shorten the time we have to determine the long term side effects of the vaccine. For Covid-19 we also do not know the long term effects of the virus itself, since it is new to humans (but has been in animals for years); therefore, there will be ongoing data collection and research long after initial approval of a covid vaccine, and we will be learning about both what the virus itself does, and the vaccine does, for years to come. To make up for the shortened trial period, many more people were enrolled in these trials, with many more comorbid conditions than in regular trials, so we can catch any potential side effects in the general population. 

Part III: Big News in Big Pharma: Pfizer says their vaccine is 90% effective. 

Two large but competing pharmaceutical companies, Pfizer (of Germany) and Moderna (of the U.S.A.), are attempting to make their covid vaccine candidates a new way. Not only are these two vaccine candidates designed to fight a new infection, Sars-CoV-2, but they are designed using mRNA (messenger RNA).

A typical vaccine takes a virus (or bacterial) toxin, or parts of the microbe that were grown in a lab, harvests it, kills it, chops it up, and purifies it until only 1 part is left, which we call the antigen. The antigen is mixed with things that help your body recognize it and defend itself against it, and that vaccine is injected either under your skin or into a muscle. Your body then mounts an immune response under the belief that these inert germs pose a real threat. Later, when the body actually encounters the real germ, it is easy for your immune system to retrieve the antibodies created in response to the vaccine, copy them, and use them to prevent or blunt the real thing’s effects.

The mRNA vaccines work by skipping the part where the lab makes an antigen. They are counting on the fact that our own body is as good as any lab at manufacturing parts of a virus. After all, that is the reason that viruses want to infect you in the first place. They can’t duplicate themselves the way bacteria can, so they trick your cells into making more viruses by hijacking their ability to make proteins. First experimented with for cancer treatment, the idea of the mRNA vaccine is to trick a few of your cells into manufacturing parts of the virus – NOT the whole virus, so it can’t give you Covid. It tells some of your cells to make the Sars-CoV-2 spike protein, for example, which is enough to make your body mount an immune response against the real virus.

Does this actually work? We don’t know yet, but in a press release on November 9, 2020, Pfizer claimed that it is working well in their data so far. Remember, in trials, half of the people receive the real vaccine they are testing, and half of them receive something else. Then everyone has to wait around and monitor the participants until people get exposed to Sars-CoV-2. They have regular visits with researchers, have blood and nasopharyngeal swabs examined, keep symptom journals, and report everything. Pfizer claims that out of the more than 44,000 people in their trial, only 94 people so far have been sick with Covid-19. When the researchers analyzed the data, they found that only nine of the people with Covid got the real vaccine candidate. The other 85 people were in the control group. That certainly looks like a pattern starting to develop. A group of different researchers ran a statistical analysis and found that if this rate continues, the vaccine would be >90% effective. This is well above the 50% floor the FDA set for approval of any COVID vaccine, moving it from being as efficacious as the influenza vaccine to put it more in line with the far more effective polio vaccine. For more information on the statistical side, check out the tweet threads linked here. 

So what are the catches? The most important is this trial is not finished, and this data came from a press release, not a journal. Only once is published can independent researchers run more analyses to validate the claims. There also haven’t been enough Covid-19 cases in the participants to know if this pattern will hold, and the FDA has said that they would not even consider an emergency application for use until there had been at least 161 confirmed cases of Covid-19 in the trial. We don’t yet know if the vaccine prevents severe disease because it was reported that no one so far has gotten seriously ill. Since this was a press release, they did not address the biases in their research, such as volunteers for the vaccine trial being more likely to wear masks and socially distance, nor confounding factors, like the participants’ socioeconomic status. Another consideration for this new vaccine type is that it must be kept very cold at -80 degrees C, and once the vaccine is thawed, it must be used very quickly. It won’t be easy to distribute it outside of a large hospital setting since it has unique storage requirements.

Another potential effect for people to be aware of and that is vaccines of this type by their very nature stimulates both the nonspecific and specific set of immune responses our body has. Your body may try to fight this “infection” with a fever and make you feel achy and tired for a few days before it gets down to building specific antibodies. That wouldn’t be dangerous, but it would be something to be aware of, or you may be afraid you’d gotten ill from the vaccine. The side effects are likely to be a bit worse than those from the annual flu shots.

In the end, it is hard to know if this is the vaccine that turns out to be the most widely used. Assuming the trend holds; however, I think it could be a useful measure to vaccinate healthcare workers who are most at risk.

A final thought added by Dr. Shaham – Update March 2021:

We now have independent analysis of the data for four Covid vaccines, from Pfizer, Moderna,  Astra Zeneca, and Johnson & Johnson. They are all effective enough to be useful in preventing severe covid disease (covid getting you sick enough to be hospitalized), with the mRNA vaccines being the most effective. They have also been used in millions of people at the time I write this, so we know they are safe, as well, with the usual caveat of side effects for 48 hours after vaccination, like fever and muscle aches, and the warning of very rare allergic reactions. I received 2 doses of the Pfizer mRNA vaccine (since that was the one given to me by my hospital, I did not favor any brand), and encourage all adults who are eligible and able to, to do the same, so that this pandemic can end.