From Need to Distribution: Vaccine Development in Urgent Times

Snow, wind, and ice—a typical mid-January Saturday in West Michigan. I was on a bus carrying 40 college students and a dozen guests as it moved cautiously on I-196 towards Chicago. “Students are going to enjoy the trip to Chicago Chinatown,” I thought, “There are so many types of Chinese cuisines to try, so many little shops carrying all kinds of gifts and souvenirs, and grocery stores selling vegetables, fish, seafood, herbs that they have never seen before.” Jacob, a tall, slim sophomore from Hong Kong, approached me, “Professor, have you heard of this new virus coming out of China?” Being a virologist and immunologist, I was immediately intrigued. Jacob showed me his phone—a news report from Hong Kong on several cases of mysterious pneumonia caused by a new coronavirus. “Another novel coronavirus!” I immediately thought of SARS (Severe Acute Respiratory Syndrome), an infectious disease that emerged in China and spread through much of Asia 17 years ago. It was caused by a novel coronavirus. Jacob probably wasn’t old enough at the time to remember anything about SARS. It appeared and disappeared suddenly. And now there was another one!

bubble tea in two glass bottles with big strawsStudents thoroughly enjoyed dining in bustling Chinatown, checking out crowded shops, laughing, chatting, sampling bubble tea, pastries, candies and snacks. What a fantastic day! A week later, I heard on the news that a Chinese woman was diagnosed with the novel coronavirus in Chicago, the second case in the US. Wow, the new coronavirus is here already! So fast! Wait, did the Chinese woman visit Chinatown when we were there?

Between my trip to Chinatown in January and now, the little mysterious respiratory disease quickly grew into a global pandemic costing hundreds of thousands of lives and millions of livelihoods. Billions of people were under lockdowns, while worrying about being a victim of the disease or the economic impact. Yet, no end to the worldwide pandemic is expected in the near future, as a matter of fact, experts expect the disease to be with us for a long time, unlike its cousin SARS. What can we do?

There is no effective treatment yet. A couple of drug candidates may be promising, the best of which so far is an antiviral drug called remdesivir that does not cure coronavirus infection, but expedites recovery. A clinical trial with more than a thousand patients showed it shortened the recovery time by 30% and reduced the number of deaths by 40%. However, more trials need to be run before we can conclude with any confidence that it works. Even then, it is not likely to be a magic bullet for all patients.

There are actually advantages in developing a vaccine in a pandemic.

Our best chance of defeating the disease and protecting lives is most likely herd immunity. Herd immunity is when enough people in the population become immune to the infectious disease, so the channels of spread are stopped. The herd immunity threshold for COVID-19 is roughly 70%. This means 70% of the population need to have immunity to stop the spread of the infection. Immunity can be achieved through natural infection or vaccination. It would be a disastrous scenario for an infection as deadly as COVID-19 to achieve herd immunity through natural infection. Assuming the estimated infection-fatality rate of 1.45%, to achieve 70% herd immunity through natural infection, it would require 3.5 million deaths in the US and 71 million deaths in the world. We cannot let that happen. We need a vaccine. In the past, we have achieved herd immunity through vaccination for infectious diseases such as smallpox, polio, mumps, measles, and rubella.

But how fast can a vaccine be developed? With COVID-19 spreading like wildfire in the world, and lockdowns unable to be sustained long term to halt its spread, do we have time? The director of National Institutes of Allergy and Infectious Disease (NIAID) Anthony Fauci said we may expect a vaccine to be available in 12-18 months. Can it be made this fast? What does it take to develop a vaccine?

Usual Vaccine Development

Let’s take a look at what it normally takes to develop a vaccine, and then apply that knowledge to our current situation to evaluate how it is progressing.

woman looking through a microscope

Exploratory Stage

During this stage, scientists identify and isolate the pathogen that causes this disease, and find out how the pathogen infects the body and causes disease. They then choose a target molecule from the pathogen to be used in the vaccine. Since there are different ways of making a vaccine, they will also decide on a vaccine platform.

Traditionally, this stage takes years, especially if the pathogen is new, like the virus causing COVID. However, in the case of COVID, this stage moved at a lightning speed. Identification and isolation of the pathogen only took a couple weeks, and identifying the target molecule(s) and making the target(s) into a vaccine candidate took place in a couple of months.

Why can we now accomplish these steps within a few months rather than a few years? Well, thanks to the years of research studying other coronaviruses like the ones causing SARS, MERS (Middle East Respiratory Syndrome), and the common cold, we now have basic understanding of the COVID virus. Moreover, vaccine platforms and development strategies have improved dramatically in the last 20 years, so making a new vaccine candidate can be quite rapid. But this doesn’t necessarily mean the vaccine candidate will prove to be safe and effective—hat still takes much testing.

Preclinical Stage

During this stage, the vaccine candidate is tested in various animal models to show that it’s both safe and effective. To do so, animals are divided into groups, with one group receiving a placebo vaccine as a control, and the rest receiving various doses of the candidate vaccine. Immune responses are then measured, and the animals are then often challenged with the pathogen to evaluate if the vaccine protects them from infection. The safety of the candidate vaccines are also assessed in toxicity studies in animals at this stage.

Overall, the preclinical stage can take several months to years. But animals are not humans. A vaccine candidate can very well work in an animal model but fail to work in humans. Before a vaccine developer can test on humans, they must obtain an investigational new drug (IND) approval from the FDA (Food and Drug Administration).

IND application

The IND application describes the vaccine, preclinical studies, manufacturing and testing process and the protocol for human studies. Once the IND is submitted and approved by the FDA, human testing of the vaccine can begin.

Clinical studies

This stage is long and complicated and can take many years to complete.

Phase 1: Testing for safety and potential immune responses

When the vaccine is tested in humans for the first time, a small number of healthy volunteers (20-80) are recruited and given the vaccine candidate to see if there are adverse effects from the vaccine. Different dosages can also be used in different groups to determine the best dosage that minimize side effects while having the best immune responses.

This phase typically takes several months. If the vaccine is shown to be safe in a Phase 1 trial, then it can move to Phase 2.

Phase 2: Testing for efficacy

In this phase, hundreds of volunteers are recruited. They typically represent the population to whom the vaccine would be given—including the elderly and those with underlying diseases. A placebo group may be included here. Immune responses or protection from the pathogen are measured and compared between the vaccine group and the placebo group to determine the efficacy of the vaccine candidate. Side effects are also tracked in this phase. Different dosages can also be tested in this phase, and compared with the placebo group.

a woman giving a vaccine to a man while 4 other people look on

This phase typically lasts one to two years. If the vaccine candidate is shown to be effective and with acceptable side effects, then it can move to Phase 3.

Phase 3: Large trials

This phase has trials on a large scale: thousands of people are recruited. A placebo group is required where people receive saline (or non-relevant vaccine) instead of the vaccine candidate. Different outcomes can be measured and compared between vaccinated group and the placebo group: 1.) Immune responses: antibody development or other immune response; 2.) Protection from disease: the number of infections/diseases are tracked over time and compared between vaccinated groups and the placebo group; 3.) Protection from severe disease: The number of cases of severe disease are tracked over time and compared between vaccinated groups and the placebo group.

At this phase, side effects are also tracked. Due to the number of people involved and the length of time required to allow infection to happen naturally, this phase typically takes years to complete. If a vaccine candidate showed efficacy in Phase 3 trials and the safety profile is also good, then it can apply for approval by the FDA. The approval process can take 10 months.

The manufacturer of the vaccine will also need to develop manufacturing capacity for a large number of doses and ensure product quality before the vaccine can be approved and rolled out for public use. Depending on the product, this step often can take years to complete as well.

Phase 4: Monitoring Use

Lastly, after the vaccine is licensed and used in public, post marketing studies are often done to further monitor the safety profile and efficacy of the vaccine. This is referred to as phase 4 studies.

COVID-19 Vaccine Development Application

Altogether, it takes on average 15-20 years to develop a vaccine, and the clinical trial stage is necessarily long to ensure safety and efficacy of the vaccine. In the case of COVID-19, there is an urgency to develop a vaccine. Can we speed it up?

The short answer: Yes we can. Since we have recently needed to develop vaccines for several newly emerged diseases urgently (H1N1 influenza, Ebola, and Zika), vaccine development capacity has dramatically improved in the last decade. Moreover, the vaccine development process is normally long because the above outlined process is usually followed sequentially—mainly for financial concerns. Companies would not want to proceed onto later, more expensive stages if a vaccine candidate has not shown promise for safety or efficacy. But in a pandemic situation, there is both a lot of incentive for rapid development and a lot of investment, so stages can happen simultaneously to save time. For example, doing animal study and human studies at the same time; starting recruiting volunteers for Phase 3 trials before Phase 2 trials are completed, or starting to develop manufacturing capability before Phase 3 tests are completed. Some clinical trial phases can be combined also: Phase 1 and 2 can be combined to test both safety and dose range. Then Phase 2 and 3 can be combined if the number of subjects can reach a high volume.

stylized coronavirus cell image

By now (June of 2020), five months from the discovery of the COVID virus, there are already about a dozen vaccine candidates in clinical trials, with some finishing Phase 2, and others planning Phase 3 trials in July.

Is it still going to be safe?

It seems in order to develop a vaccine rapidly, we are cutting corners in the process. Would we sacrifice safety by moving too fast? Yes, we certainly are taking more risks when we don’t follow the process step by step. For example, by doing animal study and human study simultaneously (for the mRNA vaccine from Moderna). They had not shown in animal study the vaccine was protective and safe for the animals, but they already started putting it in humans. However, such risks are well-calculated. mRNA vaccines are relatively safe. Since the vaccine only consists of a piece of mRNA, not a whole virus, there is no chance the vaccine recipient will be infected through the vaccine. Over the last five years, many mRNA vaccine candidates (for other pathogens) have gone through animal studies and early clinical trials to show an excellent safety profile. The mRNA platform has the advantage of conserving much of the vaccine mechanism between different pathogen targets, where the only difference would be the sequence of the mRNA. So, such a small risk is viewed favorably in light of the potential to save many more lives sooner.

So far, all the cutting-corners occur during preclinical study, Phase 1 or 2 studies. No one is saying they are going to cut corners with Phase 3 trials, and rightly so. As a matter of fact, companies plan to have tens of thousands of volunteers for their Phase 3 trials rather than just thousands. If one is going to catch some safety issues or efficacy issues, it would be in Phase 3 trials, because it has the largest number of subjects involved. Before a vaccine candidate can be approved and licensed, it will have to demonstrate in the large Phase 3 trials that it’s both safe and effective. The FDA is not going to sacrifice its standard on that.

There are actually advantages in developing a vaccine in a pandemic. For one, there will not be a lack of testing subjects. This was a serious issue with the SARS vaccine: by the time the first SARS was ready to be tested (20 months after the outbreak), the virus disappeared (and has not returned since), so one cannot run a clinical trial to test whether the vaccine is protective. Additionally, people are willing to invest money in developing the vaccine. Believe it or not, running clinical trials takes a lot of money—millions. During a pandemic, everyone sees the clear benefit and urgency for a vaccine. Then, of course, certain processes can be fast-tracked, because of the urgency. Finally, there is so much interest and so many vaccine candidates (more than 100 so far for COVID), that the chance of developing one or several successful ones is very high.

Overall, the scientific process it takes to develop a vaccine generally ensures safety and effectiveness of the final product, even when it is fast-tracked. However, for the new coronavirus, there are other challenges.

Potential Challenges for the COVID Vaccine

First of all, there may not be lasting immunity to the coronavirus, even after a natural infection. Studies have shown our immunity against coronaviruses that cause common cold fade away after several months. For SARS, the antibodies lasted several years (not lifetime), but we don’t know whether the antibody levels were protective against infection since SARS never came back. We certainly at this point still don’t know about the COVID virus. There simply hasn’t been enough time elapsed to see if recovered patients can be infected again after a certain period of time. It is possible that natural immunity to COVID may not result in long-term protection. A recent study showed that antibody levels in recovered COVID patients started to decrease within 2-3 months. If a vaccine has similar effect as a natural infection, it will require more frequent administration of the vaccine.

Secondly, there is a risk that a vaccine may cause more severe symptoms in natural virus infection. Isn’t a vaccine supposed to prevent infection, or at least prevent more severe symptoms? Yes, but some vaccines can do the opposite due to non-protective antibody responses. For example, in the dengue vaccine, it was found for some patients, getting the vaccine causes more severe disease when they are exposed to the real virus. Similar enhanced disease was observed in animal studies of certain SARS vaccines. Therefore, careful evaluation of protective versus disease enhancing antibodies is imperative during analysis of immunogenicity and safety results from COVID-19 candidate vaccines. Scientists are aware of this potential risk and will be guarding against such phenomenon when analyzing clinical trial results.

What or who can we rely on in times like this?

Anding Shen

Thirdly, immune responses may not mean protection against disease. We have seen that with HIV vaccines. After vaccination, immune responses against HIV were readily detected, but no protection against infection was observed. That is why it is crucial to test for protection against infection (or against severe symptoms) in clinical trials, rather than just testing for immune responses. Lastly, even when we develop a successful vaccine, mutations in the virus may render the vaccine obsolete. We have seen that case in influenza, and that’s why there is a new flu vaccine each year.

At this point, you may be thinking,“I am now worried. Will we ever have a safe and successful vaccine?” I understand that. The best scientific approaches, testing, and evaluation processes can guard against a lot of risks, but even the best scientists cannot tell you for sure that we are going to have a successful vaccine developed in the near future. After all, so many infectious diseases still do not have an effective vaccine, such as HIV, Tuberculosis, or malaria. What or who can we rely on in times like this?

Faith in uncertain times

Since my Chinatown trip, I went through a lot of fear and worry in the beginning. I mentally went through how I could be infected, and what I would do if I would be infected. Each person I encountered and each surface I touched became a potential threat. Daily movements were calculated to minimize risk and chance of contamination. Every piece of encouraging news about a potential treatment brought hope, and disappointment sank in when the treatment proved to be not-so-effective. The what ifs and conspiracy theories always kept me on my toes. Then, I realized my worst enemy wasn’t the virus, but my own fear and lack of faith.

squirting hand sanitizer into a hand

As Christians, our security is never meant to be found in a remedy for our problems. So many things are broken in our sin-contaminated world. “We know that the whole creation has been groaning as in the pains of childbirth right up to the present time” (Romans 8:23). If we keep on looking to the world for an answer to ensure ourselves, we will always be disappointed. Jesus said “ In this world you will have trouble. But take heart! I have overcome the world” (John 16:33). Our true hope is not in a drug or a vaccine, but in Jesus, in whom lies our true hope.

We are called to bring restoration and redemption to the broken world. Scientists and health care professionals are doing their part; so can each of us. We can help by speaking messages of hope instead of fear, trust instead of doubt, truth instead of misinformation; doing work to relieve stress and anxiety, and extend a helping hand. Be the neighbor, friend, coworker that embodies the love of Christ. In uncertain times like this, we must remember to trust in the Lord with all our hearts and lean not on our own understanding; in all our ways submit to him, and he will direct our paths (Proverbs 3:5-6).

Notes & References

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Anding Shen
About the Author

Anding Shen

Anding Shen is a Professor of Biology at Calvin University in Grand Rapids Michigan, where she teaches immunology, cell biology and microbiology. Anding obtained her PhD in Cellular and Molecular Medicine from Johns Hopkins University, where her focus was in immunology and virology. Anding’s research focus has been in HIV and AIDS, and she enjoys exploring God’s creation in cellular and molecular details with students.
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