It seems as though we hear about new approaches to vaccines for COVID-19 almost every day. This article will focus on a rather unusual one; CORAVAX™ uses the Rabies virus as a way to transport the immunity-activating molecules into the patient’s cells. The agent that causes neurological symptoms in dogs and humans turns out to be a highly effective, and safe, vector for a coronavirus vaccine. The early studies of this rabies-based vaccine successfully induced production of many antibodies neutralizing COVID-19 in each vaccinated mouse, giving a promising outlook on its effectiveness in human trials.
The urgency of anti-COVID-19 vaccine development
Since December 2019, when the SARS-CoV-2 strain first emerged in Wuhan, more than 42 million (as of October 21st) people worldwide have been affected. Along with MERS and SARS-CoV-1, COVID-19 is now known as the most pathogenic strain of the Coronavirus species by being responsible for approx. 1,131,000 deaths since the start of the pandemic.[1]
The efforts to contain the spread of the virus vary greatly between the countries, but all rely on the following principles: school and workplace closures, cancellations of public events and gatherings, stay-at-home restrictions concerning international and domestic travel, testing and contact tracing, as well as public information campaigns.[2]
Nevertheless, it is becoming clear that the government-issued regulations aren’t enough to suppress the viral spread; be it due to the high transmission rate through air droplets or the emerging defiance to follow said rules. Additionally, at this late stage of the pandemic, the so-called “isolation exhaustion” sets in, resulting in an increase of risky behaviour for the sake of social interactions. These issues are why the need for a “cure”, most likely in the form of a vaccine, is so imminent. There are currently more than 140 vaccines in pre-clinical development.[3] This article will focus on the mechanism of one of them in the context of issues encountered when developing a vaccine against SARS-CoV-2.
Why base a vaccine on a Rabies virus?
The reasons for the unusually high pathogenicity and transmissibility of COVID-19 are still unknown, however, several hypotheses are currently being investigated. One of the most probable causative agents is the spike (S) protein on the surface of the virus. In the case of SARS-CoV-2, the S protein is modified in a way that allows the pathogen to bind to an ACE-2 receptor present in the lungs, resulting in respiratory infection.[4] To confirm this assumption, scientists looked at the immune response against the virus and confirmed that the antibodies T-lymphocytes against the pathogen were targeted mostly at its S protein, making this molecule a good target for a vaccine.[5]
Now that the target for the therapy is determined, the type of vaccine must be chosen. Schnell, et al. have decided to use a viral, more specifically Rabies, vector base; the virus would act as a transporter to safely deliver the S protein into the patient’s body, where this part of the coronavirus would activate an immune response against COVID-19 without causing the actual infection.[6] Using Rabies in a vaccine seems contra-intuitive, as many of us associate it with a horrible disease. Nevertheless, there are many arguments for the use of this specific vector, i.e. it was successful in the treatment of MERS (another coronavirus species) in mice, and it’s been proven completely safe to use not only in laboratory animals, but also children, elderly, pregnant women, and immunocompromised patients.[7] The vaccine CORAVAX™ was thus designed using the Rabies vector “filled” with the S proteins of COVID-19. Additionally, to ensure that the treatment would induce an immune response, only a part of the spike protein (S1) was used; S1 is what the S protein uses to bind the ACE-2 receptor.
To test the immunogenicity of CORAVAX™, groups of SARS-CoV-2-infected mice were injected with three solutions: live Rabies virions, inactivated virions, and inactivated virions with adjuvant (a liquid solution that enhances immune responses). The serum from their blood was collected on days 0, 14, 21, 28 and 56 to measure if the mice made antibodies against COVID-19 (seroconverted). All mice produced IgG to combat the infection, and when injected with a boost CORAVAX™ after day 21 the number of those antibodies increased even more. These responses were not only immunogenic, but they were also incredibly potent; IgG concentrations were 20x higher than the ones taken from human patients that recovered from COVID-19, and even slightly higher than in a patient going through the acute phase of the infection.
How to design a vaccine against COVID-19?
Right now, approximately 30 vaccines against SARS-CoV-2 are at the stage of clinical trials; in theory, they all work, but the trials are utilized to see if they are as effective in practice.[8] For a vaccine to be successful, it must have certain characteristics and can’t have other traits.
High efficacy is the most crucial feature; the vaccine must induce an immune response to a pathogen it was designed against. One of the ways to measure this immunogenicity is to count the number of Virus Neutralizing Antibodies (VNAs). The CORAVAX™ vaccine caused the production of very high numbers of VNAs (as shown above), but not all vaccines in current clinical trials exhibit this effect. The DNA vaccine called INO-4800 activated T-lymphocytes, but they produced low numbers of VNAs.[9] A vaccine that used Adenovirus instead of Rabies as a vector couldn’t clear out all the COVID-19 particles, as the genetic material of the virus was found in the nasal swabs of the vaccinated monkeys.[10]
An additional advantage of the future coronavirus vaccine is its longevity. The therapy aims to activate the immune system in a way that it remembers the virus, so even if you get infected again, your body will use the existing defences and clear the virus before the symptoms arise. The adenovirus-based vaccines, once again, don’t satisfy another condition; a vaccine against Ebola with a very similar structure to that designed to combat SARS-CoV-2 activated the immune system for only 3 months.[11] All vaccines that had Rabies as a viral vector exhibited life-long immunity, it is thus expected that CORAVAX™ will too.
On the other hand, the vaccine cannot harm the patient; when the immune system overactivated, it may by mistake harm the cells of the host. For example, the S2 domain of the spike protein is known to bind a type of antibodies other than VNAs, which bind to the coronavirus.[12] These complexes then activate macrophages in the lungs to make them secrete cytokines - small molecules that cause inflammation.
There is another reason why CORAVAX™ uses only the S1 domain, instead of the entire S protein; all coronaviruses have very similar S2 domains. More than 90% of us have been infected by a coronavirus (one less harmful than SARS-CoV-2) during our lifetime, so we already have antibodies against the S2 domain.[13] If the S2 domain of COVID-19 was a part of CORAVAX™, the vaccine might not have activated our immune system, because it might have mistaken it with the S2 domain of less harmful coronavirus against which antibodies are already in our system.
The future
CORAVAX™ is yet another step forward in overcoming the COVID-19 pandemic. Nevertheless, the vaccine is still at an early phase of development. Though the arguments presented in the article put it in a rather positive light, it is important to note that, historically, vaccines based on viral vectors had a low success rate, the exception being the vaccine against Ebola virus.[14] To further determine the potential of CORAVAX™, studies focusing on longevity, dosage, and administration schedules of the vaccine need to be conducted. Right now, CORAVAX™ is being tested for potential toxicity, and its first clinical studies are scheduled to start this month.
The COVID-19 pandemic is taking a toll on everyone, both mentally and physically. Vaccine development is much longer than desired, however, the urgency cannot influence the process, as that would put the safety and efficacy of the potential vaccine at great risk. The aim of “the coronavirus cure” is to eradicate the virus completely, so as not to create a false sense of protection, leading to another surge in SARS-CoV-2 cases. Unfortunately, at this stage, the only form of protection is self-isolation and wearing protective equipment (i.e. masks).
Author; Maya Witowska, MSc Integrated Immunology, Keble College
References
1. Worldometers.info. 2020. Coronavirus Update (Live): 41,138,213 Cases And 1,131,156 Deaths From COVID-19 Virus Pandemic - Worldometer. [online] Available at: <https://www.worldometers.info/coronavirus/?utm_campaign=homeAdUOA?Si> [Accessed 21 October 2020].
2. Our World in Data. 2020. Policy Responses To The Coronavirus Pandemic - Statistics And Research. [online] Available at: <https://ourworldindata.org/policy-responses-covid> [Accessed 21 October 2020].
3. Mullard, A., 2020. Flooded by the torrent: the COVID-19 drug pipeline. The Lancet, 395(10232), pp.1245-1246.
4. Andersen, K., Rambaut, A., Lipkin, W., et al. 2020. The proximal origin of SARS-CoV-2. Nature Medicine, 26(4), pp.450-452.
5. Seydoux, E., Homad, L., et al. 2020. Characterization of neutralizing antibodies from a SARS-CoV-2 infected individual.
6. Kurup, D., Wirblich, C., et al. 2020. Rabies virus-based COVID-19 vaccine CORAVAX™ induces high levels of neutralizing antibodies against SARS-CoV-2. npj Vaccines, 5(1).
7. Willet, M., Kurup, D., et al. 2015. Preclinical Development of Inactivated Rabies Virus–Based Polyvalent Vaccine Against Rabies and Filoviruses. Journal of Infectious Diseases, 212(suppl 2), pp.S414-S424.
8. Who.int. 2020. Draft Landscape Of COVID-19 Candidate Vaccines. [online] Available at: <https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines> [Accessed 21 October 2020].
9. Smith, T., Patel, A., et al. 2020. Immunogenicity of a DNA vaccine candidate for COVID-19. Nature Communications, 11(1).
10. van Doremalen, N., Lambe, T., et al. 2020. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature, 586(7830), pp.578-582.
11. Stanley, D., Honko, A., et al. 2014. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nature Medicine, 20(10), pp.1126-1129.
12. Lan, J., Ge, J., et al. 2020. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature, 581(7807), pp.215-220.
13. Gorse, G., Patel, G., et al. 2010. Prevalence of Antibodies to Four Human Coronaviruses Is Lower in Nasal Secretions than in Serum. Clinical and Vaccine Immunology, 17(12), pp.1875-1880.
14. Juan-Giner, A., Tchaton, M., et al. 2019. Safety of the rVSV ZEBOV vaccine against Ebola Zaire among frontline workers in Guinea. Vaccine, 37(48), pp.7171-7177.