The European Union’s executive has announced that they will sign a contract for up to 160 million doses of the experimental coronavirus vaccine which has been developed by Moderna. This decision has been made due to the fact that the company has been transparent in respect of full disclosure of their clinical trial data.
In an effort to help protect more people against Covid-19, the clinical trials have been escalated through reducing the interval between phase I-IV trials and remove the need for the time that it takes to apply for grant applications and reviews. The objective is to deliver a safe and effective product that would grant long-lasting immunity.
It may seem like an overkill that there are currently at least 29 Covid-19 vaccines in clinical trials, all of them designed to train the immune system to fight the coronavirus by recognizing a single protein, called spike (S), on its surface. But what sets all these candidates apart from one another is the various ways that they deliver S protein, and whether they contain certain adjuvants — special molecules that rev up the immune response against the coronavirus.
Many of the vaccine candidates that were the first to enter clinical trials actually don’t contain adjuvants because they already have some built-in immune-boosting activity. For example, in the preliminary analysis, the product candidate which is being manufactured by the biotechnology company Moderna, contains genetic material (mRNA), which may have some inherent immune-stimulating capacity to crank out S protein once inside the body of the recipient to coax an immune response as a natural infection would cause.
But now that dozens of other vaccine candidates are in clinical trials and hundreds more are in laboratory studies, researchers are increasingly asking if adjuvants can do for Covid-19 what they have been doing for other vaccines for decades: guide the immune response, and produce longer-lasting immunity, whilst lowering the cost.
What we may find is that many of these adjuvants create a better vaccine, and they are all better a little differently, but they can all be useful. We will see likely waves of different vaccines coming out that have different adjuvants. It may well be the case that many of these adjuvants create a better vaccine, and be more cost effective for large scale administration as the vaccine may need to be administered more than once.
Adjuvants could boost mediocre Covid-19 vaccines
One scenario in which adjuvants could come into their own is if a research group gets its vaccine all the way through the different phases of clinical trials and determines that it is sufficiently effective. Maybe it protects half of immunized people from infection, which is the benchmark for effectiveness, but of course something closer to 60% or higher would be much better. Or maybe it induces robust levels of neutralizing antibodies, which is generally thought to be key for a successful vaccine, but levels diminish after only a few months.
We are all waiting to see the data — how good they are, and if they are partially good, we’d see companies try to make second-generation vaccines to make them better. There are various ways vaccines could be improved upon, including adding an adjuvant to an mRNA-based vaccine.
If a vaccine candidate meets the minimum criteria for effectiveness in a clinical trial, the drug company sponsoring the candidate may seek approval from regulatory agencies such as the U.S. Food and Drug Administration (FDA), or the European Medicines Agency (EMA) and in parallel they may decide to reformulate their vaccine by adding an adjuvant, or using a different adjuvant. This new version would need to pass safety and effectiveness and muster through the same series of clinical trials, which could take months to years, but if it is an adjuvant that is already in an Agency-approved vaccine and for which there is ample data, the agency may approve smaller and shorter trials.
Well-studied adjuvants in hepatitis B vaccines could also work in a Covid-19 shot
Another way that adjuvants are showing up in a big way is in preclinical studies. After the first wave of candidates that seized on speedy production and largely bypassed adjuvants, such as the mRNA-based vaccines, researchers are giving bread-and-butter technologies more of a chance. One of the established approaches, which has been used for vaccines approved for hepatitis B (hep B) virus and shingles, delivers viral protein directly into the body. Unlike mRNA and DNA, which can provoke the immune system on their own, protein slips under the radar, and so protein vaccines need help from an adjuvant molecule.
The useful thing about adjuvants is that they have more well-studied options than ever before. For alum adjuvants were the only ingredients around. Alum was first used in a vaccine in the 1920s, and is now present in no fewer than 23 U.S.-approved viral and bacterial vaccines. When new adjuvants finally started to hit the scene this century, studies suggested they might outperform alum. For example, MF59, a natural oil-based adjuvant approved for use in the flu vaccine (Fluad) for people 65 and older, elicited higher levels of flu protein-specific antibodies than alum. Another adjuvant called AS01, which is based on a harmless version of a bacterial toxin and is in the shingles vaccine (Shingrix) for adults 50 and older, led to higher levels of hep B-specific antibodies in combination with hep B antigen compared with alum, and also a stronger T cell response, which can be important for activating B cells to make antibodies. Many of these newer adjuvants have risen to the fore in Covid-19 vaccine development, but alum should still have a seat at the table because you never know which adjuvant will work best until you test it in the context of the vaccine in question.
Pharmaceutical companies share adjuvants to fight Covid-19
Although the newer adjuvants in licensed vaccines are owned by pharmaceutical and biotechnology companies, the sense of urgency for a Covid-19 vaccine has helped reduce some of the barriers to access. We should applaud GSK, which owns AS01 and other adjuvants, and Dynavax, which owns CpG 1018, used in a hep B vaccine. They said, “Here’s our adjuvant; we want to pair it with your whatever vaccine it is”. The biotech company Seqirus has also said it will make its proprietary MF59 adjuvant available to vaccine developers.
Indeed, a big focus of the preclinical work which is in laboratory models is on comparing the immune profiles of a variety of adjuvants in combination with S protein, or other proteins of the novel coronavirus, to help decide which protein vaccines to bring into clinical trials.
For example, researchers are working on a vaccine candidate containing a portion of the S protein, which Covid-19 patients have been found to develop antibodies to, mixed with alum. This formula has been shared with an India-based biotech company that is testing vaccine in combination with various adjuvants to determine which will move into clinical trials. Investigators are also evaluating segments of the viral S protein in combination with a slew of adjuvants, including from biotech companies and other academic groups, in preclinical studies. Another group based at the University of Queensland in Australia recently launched a phase 1 clinical trial of an S protein vaccine using the winning adjuvant from its preclinical research, MF59 provided by Seqirus, based on antibody levels and T cell responses.
Why the oldest adjuvant we have could end up being the best
Even with manufacturers cranking out adjuvant, experts worry that they may not be able to meet the demand for the global pandemic, which could require 7 billion doses or more. The Coalition for Epidemic Preparedness Innovations (CEPI) and the Bill & Melinda Gates Foundation have given millions of dollars to companies to help them ramp up adjuvant production. But it may not be enough, especially for the adjuvants that are in other high-demand vaccines such as GSK’s Shingrix, says Corey Casper, MD, MPH, CEO of the Infectious Disease Research Institute (IDRI), a nonprofit organization based in Seattle. IDRI has provided its own offering of adjuvants, both synthetic versions of the adjuvants that are in licensed vaccines and novel molecules it developed to Covid-19 vaccine developers at low cost for testing in preclinical studies. IDRI would be co-owner of vaccine technology using its adjuvant.
The supply issue is one of several reasons the oldest adjuvant, alum, which is widely available and affordable, may end up being among the chosen ones. However, the most important point in its favor is that it has a long history of safety and effectiveness. If alum leads to high levels of antibodies but does not elicit sufficient T cell responses, it could be combined with another adjuvant, to promote the immune response. This approach could also lower the cost of the vaccine because alum can lower the amount of costly antigen needed. Each adjuvant has its role.
Until such time that a safe and effective vaccine becomes widely available for all, the best weapon that we have against infections is to improve one’s innate immunity through the well-proven means of a balanced diet and exercise. In some respects, the coronavirus epidemic has given us all a wake up call. In the meantime, it is hoped that researchers will balance the bread-and-butter adjuvant, and bread-and-butter vaccine technologies, with the new and enhanced methods of protecting the public’s health.
Colbé Trust 