The Milken Institute launched a tracker with which you can follow progress in the development of drugs and vaccines for COVID-19. As of May 11, the tracker lists 125 vaccines in development around the world. Below, I provide a summary of what is going on. I first highlight the challenges of quickly developing a vax. Then, I give you a sample of some of these efforts and discuss some of the ingenuity that is going into these efforts around the world.
Challenges: An immediate challenge with fully developing a vax is being able to test it before the pandemic fizzles out on its own. That is what derailed the full development of the SARS and MERS vaccines. In a vaccine trial, you have to wait for people to be naturally exposed to the virus in order to learn whether the experimental vax is effective. Since there is no effective treatment for COVID-19, it would be highly unethical to deliberately expose test subjects to the pathogen in order to see if a test vax protected them. If the pandemic fizzles before a vax can be fully tested, we will never know how effective any of the 125 vax candidates are.
Yet, there is the very real threat that we will see a second and maybe third wave of the pandemic that would naturally generate new infections for the vaccine trials. Also, while the pandemic might be on the downswing in Europe, it seems to be catching fire in India and Africa and places in the Southern hemisphere. For this reason, vax researchers are partnering with health scientists in places of the world where the pandemic is expected to soon take off. Therefore, there might be enough “life” left in the pandemic to fully develop and test a human coronavirus vaccine. But, it is something hard to hope for.
Another potential concern is uncertainty regarding what kind of immune response an experimental vaccine would generate in people. We have to make sure that the immune response does NOT exacerbate the problems of the COVID-19 disease. That is a real concern since we know that the immune response to Dengue virus can actually enhance its ability to infect cells. Also, a very recent paper from MIT scientists indicates that a cytokine called interferon produced by immune responses can actually increase the level of expression of the viral receptor in human cells. That means that the immune system might make it easier for the virus to infect cells. Earlier animal studies to develop a SARS vax showed that animal test subjects often fared worse after immunization.
As I discuss below, we will soon know the answers to these questions.
Progress: With these challenges in mind, scientists around the world plod on to develop an effective vaccine as quickly as possible. These are scientists more used to the long-term development of vaccines and therapies that go into humans. Now they are like marathon runners having to learn how to sprint.
- Perhaps the lead vaccine candidate at this point is being developed by investigators at Oxford University in England. Years earlier they developed a vax candidate to MERS that showed good promise in early clinical trials. Their approach to the MERS vax is being repeated for the CoV-2 vax. This entails inserting the CoV-2 spike protein, which is what gives the virus its corona appearance, into a crippled form of an adenovirus that causes common colds in humans. The crippled adenovirus was genetically engineered so that it can infect human cells, but not spread or cause illness. This “fake” virus makes the immune system think that the body is infected with CoV-2 and respond to that molecular sleight of hand.
The crippled virus was tested on six monkeys at the US NIH Rocky Mountain Laboratory in Montana. Vaccinated and unvaccinated monkeys were then challenged with live CoV-2 virus. 28 days later the vaccinated animals were completely protected from the virus and showed no illness while the unvaccinated animals became very sick.
Based on this encouraging, but extremely small preclinical study, the Oxford team has recruited and vaccinated about 1000 volunteers in order to assess safety and to determine the type of immune response generated by the vax. It is a blinded, placebo-controlled trial where one-half of the subjects received the CoV-2 vax and the remainder received a control vax against unrelated meningitis. The investigators anticipate releasing the results of this initial safety trial by the end of next week. If things go well, they plan to recruit another 5000 patients by the end of the month for efficacy trials. At this aggressive pace, they hope to have a fairly good idea if the vax is safe and effective sometime in September. Whew!
The most innovative aspect of this effort is not in the science, but in the more mundane area of product development. Even while this lightning-fast R&D is still underway and the vax still uncertain, the biopharma company, AstraZeneca, has agreed to begin large scale production of the vaccine with no guarantee that it will ever work. They say that there will be 100 million doses of the experimental vax by the summer and 1 billion doses by the end of the year. For context, several pharma companies together produce about 150 million vaccine doses each year to deal with seasonal influenza in the US. Thus, a single company producing 1 billion doses in about 6 months is unprecedented and represents a huge risk if the vaccine fizzles or if another lab develops a better one.
The idea is that if the vax does prove to be effective, it will be immediately available for dissemination around the world without the normal delay of ramping up production and distribution capacity. Other companies have said that they also will begin large scale production of other experimental vaccines while they are still under development. Most of these vax candidates will fail, which means that the pharma companies are assuming huge risk in order to make sure an effective product gets out into the world as quickly as possible. That is unheard of.
- In April, Chinese scientists from a biotech company in Beijing developed an “old-school” inactivated viral vaccine. This is the intact CoV-2 virus itself that has been chemically “killed” or inactivated. Typically, a solution of virus is inactivated by treating it with formalin. The formalin is dialyzed out from the now inactive virus, which is then used to vaccinate people or animals. This was the way that most early viral vaccines were developed and has been quite successful, although not always. A monkey trial published May 6 in the journal Science indicates that this inactivated CoV-2 virus is safe and fully protected them from a challenge infection with live virus. The Chinese lab says that placebo-controlled human trials are underway in Jiangsu province, which is north of Shanghai.
- In the US and Germany, the pharma company, Pfizer, and its biotechnology partners have human trials underway to determine the safety and immune response to four novel vaccine candidates. This effort uses a totally unique vaccination approach that has never been used to prevent any infectious disease. Most vaccines use crippled or killed virus, or “pseudo-viruses” that have been genetically engineered to express select viral proteins that can potentially be recognized by the immune system. These inactivated, crippled or “pseudo-viruses” trick the immune system into thinking that there is an active infection.
In contrast to these standard approaches, Pfizer, as well as biotech companies in Seattle, Pennsylvania and elsewhere are developing totally novel RNA or DNA-based vaccines. RNA and DNA are the genetic material viruses use to express proteins that the immune system recognizes and responds to. The idea is that if genetic material encoding these proteins enters human cells, the cells will use the genetic information to make select viral proteins without producing any virus. Again, this should trick the immune system into making a response that, hopefully, will protect against future infection with the live virus.
Results on the safety of this initial Pfizer trial involving 360 subjects should come early next month. If the results are encouraging, larger trials to test the efficacy of the vaccine will be launched. The other three vaccines in development will also soon begin human trials. Ultimately, the most promising vax will be moved forward. Depending on the results of these studies, Pfizer believes that a vax could be ready for emergency use as early as this fall.
- In Madison, WI, investigators at FluGen and the University of Wisconsin (disclosure: the author is retired from the University of Wisconsin Medical School) are working on an innovative flu/Cov-2 vaccine combination. FluGen has already developed a crippled flu vaccine candidate that consists of a live flu virus that has been genetically engineered to be able to infect cells, but not to spread or cause disease. To this “vehicle,” investigators added the CoV-2 spike protein gene so that cells infected with this engineered, defective virus will stimulate immune responses to both flu and CoV-2 molecules. Also, unlike most of the 125 CoV-2 vaccines in current development, this combination vaccine candidate will not be injected, but will be given as a nasal spray in order to better mimic the major route of exposure to both viruses. Vaccine exposure to mucosal membranes generates a somewhat different type of immune response compared to vaccines that are injected. The idea is that a nasal vaccine might produce a more relevant immune response to stop the viruses in the mucosa before it can ever enter the lungs and other organs. A clinical trial of this vax is expected to happen in India by August.
Bottom line: Stay tuned. My view is that these aggressive predictions for finding a safe and effective virus are overly optimistic and if a vaccine is possible, it will take quite a bit longer to find.
I would be very happy if I was wrong.