Last updated August 10th 2020, 5:28:24pm

Why are there so many vaccines being developed for COVID-19? What is the difference between each? Which vaccines will succeed and which will be ready first?

To understand how vaccines work, we’ll first need to quickly review some immunology fundamentals; for more, see our Path of the Virus explainer.

When your immune system meets a viral threat, it begins fighting with a generic response, which is not specific to any particular virus. But over the first one to two weeks after infection, your adaptive immune cells kick in. These cells are specialized for the particular virus you are fighting; they can learn to recognize specific structures of the virus (called antigens) and train to effectively kill them. These cells produce antibodies, which you’ve probably heard a lot about lately. Antibodies are large proteins created to target and stick to the antigens on the virus, and kill it.

Importantly though, the adaptive immune cells do more than just produce antibodies to kill the current virus. Some of these cells also become “memory cells,” long-lived cells that remain in your body, ready to quickly ramp up a fight against re-infections of the same pathogen. These memory cells, along with antibodies which also stay around in your body, are key to viral immunity.

All of this describes what happens if you actually become infected with a virus, like SARS-CoV-2. But this also parallels how vaccines work. The goal of most vaccines is to simulate the infection in a safe manner so your body will produce memory cells that will be ready if the actual infection occurs. This is how the annual flu vaccine works.

To do this, the vaccines have to somehow mimic the virus so the immune cells can undergo the learning process and train to target its antigens. Then, the key question for vaccine development is: how do you simulate an infection without actually infecting people with the virus?

There are a number of different approaches for vaccine development. The techniques can be broadly divided into four categories: (1) killed/weakened virus, (2) viral vector, (3) nucleic acid, (4) protein-based. We’ll give an overview of each and their significance for COVID-19.

Types of Vaccines

Killed/Weakened Virus Vaccines

This method, the most traditional, involves using the virus itself as a vaccine. Basically, these techniques introduce the virus into the body, so the body can produce antibodies and memory cells pretty much the way it would normally do. You may ask: “How could you possibly do this safely?” The answer is that the virus must be weakened enough that it cannot successfully infect cells, but not so much that it loses its structure. This way the adaptive immune cells can still see the viruses’ antigens and make memory cells poised to respond if there is exposure to the real SARS-CoV-2.

There are multiple ways to weaken the virus. One method is to grow the virus in cells of other animals. The virus will be tricked into mutating in a manner that allows it to better infect those cells instead of human cells. A second method is to use heat or chemicals to weaken the virus. Both of these methods result in a virus that is safe and does not harm humans, but still has the antigens that adaptive immune cells can learn to target. Measles, polio, and some flu vaccines are three prominent examples that use weakened or killed viruses.

Take-home point: this method is how humans have been making vaccines for the past 100 years and it works for many diseases, but they take a lot of effort to manufacture!

Viral Vector Vaccines

Memory cells and antigens are formed to target the antigen portion of the virus. However, the antigen alone doesn’t make you sick. This means that if you could somehow introduce the antigen into your body, without the rest of the virus, you might be able to get your body to make memory cells without getting sick.

This is the basic idea behind the other three vaccine approaches. They differ in how they introduce the antigen. First up: the viral vector approach, in which a live, genetically engineered virus is used to introduce SARS-CoV-2 DNA to our cells.

The goal of this method is to hijack our own cell’s machinery to make SARS-CoV-2 antigens. The key to this method is the use of a different, controlled virus to deliver SARS-CoV-2 DNA into our cells. Your cells are designed to be hard to break into. Viruses, though, are really good at getting in (this is part of the problem!). But in this case we can use a virus that’s safe as a way into the cell. Scientists have learned how to control and use certain viruses as “vectors” to deliver specific DNA to our cells.

So what can our cells do with the DNA? These DNA encode SARS-CoV-2 antigens and our cells can use it as a recipe to start producing antigens. This response trains the adaptive immune cells and forms memory cells.

Over the last few years, the method has been used more frequently—two Ebola vaccines have been developed using viral vectors. It has some limitations (for example, if you’ve already been infected with the virus that is used as a vector, this will not work), but it is an area of active research.

Take-home point: viral vectors are promising, but not the most battle tested type of vaccine.

Nucleic Acid Vaccines

Nucleic acid vaccines work on the same principle as the viral vector approach, but with a different delivery vehicle. One way this is done is with an oil-like structure which can pass through human cell membranes without disrupting them. Another approach, called electroporation, uses electric shocks to briefly open up small holes in our cells, allowing DNA to enter. In either case, once the DNA is inside, our cells begin reading the DNA instructions and produce SARS-CoV-2 antigens.

As the newest mode of vaccine design, no vaccines have yet been approved with this approach; however, several COVID-19 vaccine candidates using this approach have shown promising results (of note, the Moderna vaccine). One of the biggest advantages of nucleic acid vaccines is the impressive speed at which they can be designed, allowing researchers to quickly produce potential vaccine candidates.

Take-home point: nucleic acid vaccines will be easier and faster to develop, but are untested at this point.

Protein-Based Vaccines

Finally, we have a more direct approach for introducing antigens into your body: a protein-based vaccine, which directly provides your body with SARs-CoV-2 antigens. This straightforward approach avoids obstacles in the delivery of viral vector and nucleic acid vaccines, and because only a non-infectious portion of the virus is added, there is no risk of infection.

One potential problem here is antigen manufacturing. In the previous two vaccine methods, antigen-coding DNA is given to our cells, which then make the antigens. In the protein-based method, the antigens have to be produced outside our body (i.e. by a vaccine company), which may slow things down.

Another challenge to protein-based vaccines is that when antigens are added directly, our immune system may need to be stimulated in parallel to respond and start making memory cells. Additional ingredients called adjuvants are added to the vaccine to elicit this response. Adjuvants are well understood chemicals, but adding additional ingredients means more development challenges.

When done well though, this approach has been shown to be highly successful. For example, Hepatitis B and some flu vaccines use this method.

Take-home point: protein-based vaccines are harder to manufacture but have many examples of successful vaccines.

Current Vaccine Progress

Vaccine Pipeline

Before any vaccine is used on a human, scientists first need to show evidence that it will be both safe and effective. This relies on laboratory testing, frequently using animals such as mice and monkeys. In the United States, the FDA oversees approval for clinical trials. In normal times, the preclinical phase of development takes years.

If a vaccine successfully protects animals in these “preclinical” experiments, scientists move on to clinical trials with humans. These trials usually proceed in three phases:

  1. Phase I tests safety and optimal vaccine dosage. A small number of healthy volunteers receive the vaccine at a variety of doses. Participants are monitored for the development of side effects. Traditionally, this phase lasts between 6 months to a year. Vaccine efficacy is not evaluated at this stage. If it is deemed safe, the vaccine will be approved to go to Phase II trials.
  2. Phase II begins to test efficacy using the same dose in a larger group of people (on the scale of tens to hundreds), including those who are ultimately intended to receive it. In the case of COVID-19, this may include people who are elderly or who have comorbidities that put them at higher risk of severe disease. Most trials apply the optimal doses determined from Phase I. Like Phase I, this phase typically takes six months to a year to complete.
  3. Phase III, the largest and longest phase, tests efficacy in a very large group of individuals, often hundreds to thousands of people across multiple locations. The selected individuals are often “high-risk individuals”—for example with COVID-19, think nurses and doctors or the elderly. The trials themselves are typically randomized controlled trials, meaning that the vaccine candidate is compared with the current standard of care for the disease. In cases where a current vaccine isn’t available such as with COVID-19, a placebo vaccine will be used on some individuals. Vaccine efficacy will then be judged on how many people were infected relative to the placebo group.

Typically, very few vaccine candidates successfully complete this pipeline. However, if one does, it is ready for general clinical use.

Obviously, these timelines are slow. In the case of COVID-19, they are likely to be dramatically accelerated. The FDA is determining which vaccines can go on to clinical trials (without preclinical animal testing) oftentimes based on previous safety and efficacy data of the type of vaccine that is being proposed. Many companies have combined trial phases into Phase I/II and II/II. Additionally, multiple initiatives, including ones from the Bill & Melinda Gates Foundation and the NIH as well as Operation Warp Speed have been launched to further speed up development and access to vaccines.

Current Vaccine Development

As of July 20th, there are over 160 vaccines in development, with 26 of them in human trial phases. For a continuously updated tracker of vaccine candidates, check out BioRender and the NIH website. There are many different groups developing vaccines and it can be difficult to predict which candidates will succeed, as it is common for many vaccines to fail during one of the phases (due to problems with safety, efficacy, or other things). Here, we’ll highlight a few candidates that are at the forefront of the clinical trial phases and are worth watching.

Most Advanced and Promising Vaccine Candidates (as of this writing, 7/20):

A group at the Jenner Institute of Oxford University in the UK is employing a chimpanzee adenovirus to make a COVID-19 vaccine (this is an example of a viral vector approach). On July 20th, they reported promising results of their PhaseI/II trial. The results indicate that their vaccine produces an increased antibody and immunological response, and that this response can be maximized with a second “booster” dose. The vaccine produced no severe side effects in all 1077 subjects (although mild side effects included fever and headache were widespread, researchers believe these can be managed with Tylenol). The results of this study show that the vaccine effectively induces a protective response and is safe, but they do not yet confirm whether the vaccine can prevent people from becoming infected with COVID-19. Phase II/II trials in England as well as Phase III trials in Brazil and South Africa (where cases are higher) will investigate the effectiveness of the vaccine in preventing infection and illness. The results of the Phase I/II trial are extremely encouraging, and the UK has already ordered 100 million doses of the vaccine that, by optimistic predictions, could be ready by the end of the year.

China announced late May via social media that a vaccine candidate by the Wuhan Institute of Biological Products and the Beijing Institute of Biological Products may be ready by late 2020 or early 2021, another one of the more optimistic predictions. These researchers are employing a killed/weakened virus and are currently in phase II of trials. While this inactivated virus method often provides the most robust immune response (since the virus vaccine better represents the actual SARS-CoV-2), the development process is typically longer than other approaches. Extra care may be needed to verify its safety.

The US company Moderna is developing a vaccine that delivers mRNA instructions for the SARS-CoV-2 spike protein to our cells. On May 22nd, they were the first company to report results showing that people who were given the vaccine produced antibodies against the virus. The results were widely interpreted as positive and sent stock prices surging. The full data was released on July 17th and showed that volunteers who received the vaccine made more antibodies than most patients who had recovered from COVID-19, but that a second injection four weeks after the first is required to produce this dramatic immune response. Dr. Anthony Fauci regarded these results as “quite promising". Volunteers for the large scale Phase III trials can now sign up through The COVID-19 Prevention Network. The Moderna trial is scheduled to begin on July 27th. 30,000 people will be randomly assigned to receive either an experimental vaccine made by Moderna or a placebo. The company is hoping to have vaccine doses ready in early 2021 (Read our interpretation of Moderna’s results here).

Other Vaccines in Pipeline:

The American pharmaceutical company Johnson & Johnson has developed a vaccine candidate employing adenoviruses, a different type of virus, as the delivery vehicle to deliver DNA that encodes SARS-CoV-2 spike protein. They launched Phase I/II trials in July and have already begun increasing manufacturing capabilities in hopes of in-human clinical trials in September. They published results in late july showing that their vaccine protects monkeys against infection after just one dose.

Another American company, Novavax, has developed a candidate that includes the administration of a proprietary adjuvant, already shown to be safe, to encourage the activation of immune cells that help mediate memory cell formation. The company has shown their vaccine can successfully generate antibodies against SARS-CoV-2 in animals and has begun their first human clinical trials in Australia. If trials are successful, Novavax hopes to deliver 100 million doses in the US by early 2021.

Caveats and Concerns

The speed of vaccine development in COVID-19 is unprecedented. Because of the desire to go fast, most of the vaccine development has focused on newer technologies, not the traditional weakened virus approach. These newer technologies have to pick a particular protein to focus on, and all of the candidates in development target the same protein in SARS-CoV-2: the spike protein, or S-protein. The differences across technology are largely in how they deliver instructions to your cells for how to make it.

The biomedical community is developing S-protein based vaccines because research in SARS and MERS suggests that an antibody response to S-protein could be protective, and we know that the S protein plays a key part in the induction of antibodies. However, we don’t know for sure that it’s going to work.

At least some scientists are worried that we have all of our eggs in one S-protein basket, so to speak. We are relying on an assumption that the immune response to the S-protein works—and while this is an assumption based on promising data, it could still be wrong. If raising a vaccine mediated immune response to S-protein doesn't provide protection (regardless of the different delivery technologies) we could be months to years behind.

It is worth keeping in mind that a successful vaccine will not function as an off-switch to the pandemic. Producing and distributing a vaccine will depend on and strain our distribution networks, supply chain, global cooperation, and public trust. The FDA has agreed to approve a vaccine so long as it is at least 50% effective, meaning all vaccinated patients won’t have guaranteed immunity. Additionally, no single vaccine manufacturer can produce enough doses to vaccinate the planet at the timescale that we need. In order to vaccinate a large proportion of the global population, we will need to see several vaccine candidates succeed. That said, many vaccine companies have already partnered with manufacturing companies to ensure optimum production capabilities are where they need to be if their vaccine is successful—meaning distribution to millions of people as quickly as possible.

Bottom Line

Progress is being made on vaccine development at an unprecedented rate. Many different companies are racing towards the same goal through different approaches, which provides some (but not perfect) hedging against failure of a single candidate. A process that usually takes years is being condensed into months. Vaccine companies have partnered with manufacturing companies before they’ve seen positive results to ensure high production capabilities.

As different vaccine candidates are being accelerated through the pipeline, companies and government agencies must still ensure safety in addition to efficacy. Dr. Fauci expressed “cautious optimism” in late May regarding the results of Moderna’s vaccine trials and said that it’s possible for a vaccine to be ready by the end of 2020. Additionally, China predicted on May 29th that they might also have a vaccine ready in late 2020 or early 2021. Earlier predictions put this best case scenario time frame later than this —perhaps early summer 2021.

It is important to stress that any predictions like this are, at best, guesses in the dark. We all want a solid timeline to grasp and hope for, and “we just don’t know” as an answer is unsatisfactory—but we really just don’t know. It’s possible that the successful vaccine candidate has not yet been created. Efficacious vaccines are often not safe. Safe vaccines might not be effective. Vaccines that work in monkeys often don’t work at all in humans.

It is also important to note that as the number of COVID-19 cases decrease, efficacy of the various vaccine candidates will be harder to judge because a company will have a harder time determining whether the vaccine is effective or if there are simply fewer incidences overall due to social distancing practices.

Will this extend the timescales of the trials? Will the currently accelerated trials compromise safety? How long will it take to upscale manufacturing capabilities and produce enough doses? The speed of progress is encouraging, but we’ll need more time to answer these questions for certain.