Labs around the world are trying to develop a vaccine to stop the rapidly spreading novel coronavirus that causes COVID-19 (coronavirus infectious disease 2019), because this potentially deadly virus is unknown to the human immune system, making us completely vulnerable. As of the writing of this post on April 10, 2020, the Johns Hopkins University of Medicine Coronavirus Resource Center indicates 1,619,495 cases of COVID-19 worldwide, along with 97,200 deaths. Also as of today, in the U.S. there have been 466,396 cases (doubling in the last 10 days), and 16,703 deaths. It is a serious pandemic, and we still do not know how this will end.
Know thine enemy
Coronaviruses were detected in the 1960s, and were probably around a long time before that. This family of viruses can infect people and/or animals, and may cause epidemics of community-acquired upper respiratory tract infections (URI), or sometimes diarrhea. The coronavirus subfamily can be divided into four genera: alpha, beta, gamma, and delta. The human coronavirus (HCoV) genera taught when I attended medical school were the alpha coronaviruses (HCoV-229E and HCoV-NL63) and beta coronaviruses (HCoV-HKU1, HCoV-OC43).
Until 2002 coronaviruses were thought of as generally benign. Consider the quote from the 1996 Medical Virology textbook I still have, which described the typical coronavirus infection this way: “The illness lasts about a week and is of no real consequence.” It was known back then that coronaviruses tended to cause colds mainly in the winter and early spring. In human volunteers whose nasal passages were swabbed with these viruses,incubation took 2-5 days, and in about half symptoms would develop, and virus would be shed for about a week. (1) Prior to 2002 it was thought that infection with the “benign” human coronaviruses would result in a form of immunity to reinfection, but that this would last only 2-3 years. Thus, people would be reinfected every few years.
Starting in 2002 the beta genera of coronaviruses were joined by new deadly members.
SARS was caused by SARS-CoV (severe acute respiratory syndrome coronavirus), which began November 2002 in China, and by 2003 was responsible for the infection of 8098 people, and claimed 774 lives. There was a massive containment strategy in the east, (and in the few cases that made it to the U.S.). SARS seemed to have vanished from the human population since 2003.
MERS was and is caused by MERS-CoV (Middle East respiratory syndrome coronavirus), and erupted in the Arabian Peninsula in 2012. Though the initial outbreak was contained, the virus has since been endemic to camels, occasionally infecting humans (zoonotic transmission), and these “super-seeders” then spread the disease in local outbreaks. From 2012 – November 2019 MERS has caused 2494 cases, and claimed 858 lives.
The virus that causes COVID-19 is a type of coronavirus called SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2). It is the newest member of the coronavirus family, and is thought to have jumped from a species of bat (likely sold in a seafood market in Wuhan City, China), to the human species. As yet there is only one serotype of SARS-CoV-2 reported in the literature.
Serotypes are groups within a single species of microorganisms, such as viruses, which share distinctive surface structures. These surface structures are usually proteins or glycoproteins that the virus uses to infect certain cell types in the body. Think of them like keys that fit into certain locks. These proteins are important, because the human immune system also recognizes them. They tend to be very specific to the virus only. If your immune system encounters some of these proteins, it knows they do not belong, and therefore the virus particles are invaders. In the case of people who have survived an infection, the immune system has targeted these structures, usually by making antibodies. Antibodies, as discussed in the last post, are part of our defense against viruses. Direct infection and recovery seems to be the most effective way to gain immunity against an infection, but in the case of COVID-19, the risk associated with having an infection is high. It would be better to have a vaccine.
How do vaccines work?
In the case of a virus with a single serotype, all of those viruses are essentially identical. When infected with the virus, the immune system makes antibodies against that serotype, remembers that target, and therefore creates immunity. When there is more than one serotype, surface structures vary: one way for a virus to evade detection.
In terms of vaccine production, having a single serotype is a good thing. SARS-CoV-2 appears to only have one serotype. A modern approach is to put the protein of interest in a vaccine. Researchers often use the spike protein, which is what allows the virus to enter the cell it infects. If you can inject that protein the immune system may make antibodies that block the spike protein on the virus of interest. Thus, the virus cannot infect the cell, and the vaccinated person will be protected. This is the basis of the hepatitis B virus (HBV) and the human papillomavirus (HPV) vaccines. With the HPV vaccine the protein is made in a yeast cell (via genetic engineering), and is identical to the protein on the surface of the virus-pretty clever. There are a variety of strategies that can be used to induce an immune response against a certain viral glycoprotein.
Vector vaccines (the basis of the dengue and Ebola vaccines) use a harmless virus such as an adenovirus, which is altered in the lab to contain a gene that codes for a surface protein such as the spike protein. The vector vaccine cannot replicate, but for a short time causes expression of the protein and thus, the immune response.
RNA vaccines are faster and cheaper to produce, and safer than traditional vaccines. RNA vaccines take advantage of a process that cells already use. Under normal circumstances cells use their own DNA as a template to make messenger RNA (mRNA) molecules, which are then translated to build proteins. An RNA vaccine contains a mRNA strand that codes for a disease-specific molecule, such as a spike protein. Once inside the body’s cells, the viral protein will be made, placed on the surface of a cell, and recognized as foreign by the immune system. This will cause an immune response.
There are DNA vaccines as well. The problem is in selecting the right protein or glycoprotein target. The spike protein may be an excellent and effective target, which will usually produce neutralizing antibodies. Sometimes the wrong protein is chosen and a binding antibody is made, which may be ineffective, or even harmful. This is why animal models are needed, and why research and development is so slow.
Historically, it has taken an average of 10 years for a vaccine to go from development to use. (3) However, the U.S. Department of Health and Human Services took steps on March 30 to speed up development and manufacturing of vaccines to prevent COVID-19. And, the World Health Organization has developed a blueprint for disease models in lab animals.
The Coalition for Epidemic Preparedness Innovation (CEPI) is an international nongovernmental organization funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission, and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway, and the United Kingdom). CEPI supports development of vaccines against five epidemic pathogens on the World Health Organization (WHO) priority list, including COVID-19.
The genetic sequence of SARS-CoV-2 was published January 11, 2020, by Chinese scientists. In what must be record speed, the first COVID-19 vaccine candidate started human trials March 16, 2020. As of this week there are 115 vaccine candidates across 19 countries, and the U.S. leads with 46%. (2) In clinical development are:
- mRNA-1273 (Moderna), mRNA SARS-CoV-2 spike protein
- Ad5-nCoV (CanSino Biologicals), adenovirus expressing spike protein
- INO-4800 (Inovio), DNA plasmid encoding spike protein
- LV-SMENP-DCpathogen-specific aAPC (Shenzhen Geno-Immune Medical Institute), selected viral proteins
Moderna began clinical testing of its mRNA-based vaccine in mid-March. The plan was to enroll 45 healthy adult volunteers in Seattle, Washington age 18 to 55.
There are other licensed vaccines based on recombinant proteins and existing large-scale production capacity already in place for those vaccines. It might possible to scale up production for a similar SARS-CoV-2 vaccine quickly. Most of the candidates seem to induce neutralizing antibodies against the viral spike protein, which would prevent viral uptake by the human ACE2 receptor.
CanSino has moved its trial into phase II with 500 people as of today, after only three weeks in phase I with 108 healthy volunteers in the city of Wuhan.
Conclusion
These are just a few thoughts about vaccines. This is not an area in which I work, but one which is of course very interesting to all of us. I’m sure there will be a lot to come, and I hope the vaccine trials are successful and safe for those human volunteers, who have my deep admiration.
REFERENCES
- Wege, et al. The biology and pathogenesis of coronaviruses. Curr Top Microbiol Immunol. 1982;99:165-200.
- Le, et al, The COVID-19 vaccine development landscape. Nature Reviews Drug Discovery. doi: 10.1038/d41573-020-00073-5 https://www.nature.com/articles/d41573-020-00073-5
- Pronker, et al. Risk in Vaccine Research and Development Quantified. PLOS ONE https://doi.org/10.1371/journal.pone.0057755
