On Study Tour in February, just two weeks before we were quarantined in Denmark, my Medical Biotechnology and Drug Development course visited a vaccine research group led by Professor Sarah Gilbert at the Jenner Institute at Oxford University.
Here, the students were introduced to a new COVID-19 vaccine named ChAdOx1 nCoV-19, one of the most promising and furthest ahead vaccine candidates being tested in humans in the world today.
I’m Jeanette Wern, immunologist with experience in vaccine research, and I teach in the Biomedicine program at DIS Copenhagen.
What are coronaviruses really?
Coronaviruses are a large family of viruses that are common in both humans and animals that usually cause mild to moderate upper-respiratory tract illnesses, like the common cold1. However, in recent times, three new coronaviruses have emerged from animal reservoirs causing serious and widespread illness and even fatal disease. SARS coronavirus-1 (SARS-CoV-1) emerged in 2002 and caused severe acute respiratory syndrome (SARS), but by 2004, the virus had disappeared. In 2012, MERS coronavirus (MERS-CoV) emerged causing Middle East respiratory syndrome (MERS) and continues to cause sporadic and localized outbreaks.
The third novel coronavirus to emerge is named SARS-CoV-2. It causes coronavirus disease-19 (COVID-19), and spreads via respiratory droplets from coughs and sneezes and indirect contact with surfaces where it can remain viable for up to three days. It was declared a global pandemic by the World Health Organization (WHO) on March 11, 20201.
How does COVID-19 compare with Influenza? Why can both jump from animals to humans?
Influenza and COVID-19 are both infectious respiratory illnesses, that can be mild or severe, even fatal in some cases2. The two illnesses are caused by different viruses and while COVID-19 is caused by SARS-CoV-2, the flu is caused by any of several different types and strains of influenza viruses2.
Both SARS-CoV-2 and influenza are RNA viruses, which are characterized by having a very high DNA mutation rate. This results in small random changes in how the virus looks, enabling the viruses to escape our immune system as immune cells cannot recognize the continually changing virus. This is also the reason that drug resistant viruses sometimes develops.and why the viruses can evolve from an animal infected pathogen to a human infected pathogen – occasionally causing pandemics[1]. Let’s not forget that over the past 100 years, there have been four flu pandemics: 1918 Spanish flu3, 1957 Asian flu, 1968 Hong Kong flu, and 2009 swine flu.
When do we expect to have treatments for COVID-19?
We have anti-viral treatments for the flu, that can decrease symptoms and sometimes shorten the duration of the illness2 and each year new influenza vaccines are developed to reduce the severity of the flu particularly for the elderly population and immunosuppressed individuals2. In contrast, the mortality rate of COVID-19 is thought to be higher than most strains of influenza because people do not have any immunity to it and, importantly, because only one treatment4 and no vaccines are available at this time, though many are in progress5.
Anti-viral medications and other therapies are currently being tested to see if they can address symptoms. As of April 19, The Food and Drug Administration (FDA) said there are currently 72 active trials of therapeutic agents and another 211 development programs in the planning stages6. Rather than coming up with compounds from scratch that may take years to develop and test, researchers and public health agencies are looking to repurpose many drugs already approved for other diseases and known to be largely safe. Drugs that have not been licensed yes, but have performed well in SARS and MERS animal studies are also evaluated.
On March 20, WHO announced a large global trial, called SOLIDARITY, which is a multi-country clinical study for potential treatments for COVID-197. While randomized clinical trials normally take years to design and conduct, the Solidarity Trial will reduce the time taken by 80% by using simplified procedures and no paper work required. As of April 21 2020, over 100 countries are working together on testing four different drugs or combinations: 1) Remdesivir, an Ebola treatment that has generated promising results in animal studies for MERS and SARS 2) Lopinavir/Ritonavir, a HIV treatment 3) IFNb-1a, a multiple sclerosis treatment and 4) Chloroquine and Hydroxychloroquine, which are closely related treatments for malaria and rheumatology conditions, respectively7.
May 1, FDA granted emergency authorization for the use of Remdesivir as a treatment of severely ill patients4. Remdesivir only showed modest success in a federally funded clinical trial, slowing the progression of the disease, but without significantly reducing fatality rates. However, this is still better than no treatment at all.
How does our immune system respond to SARS-CoV-2? Are we protected after an infection?
The best strategy to move out of this lockdown state that most countries are in, seems to be increased testing and possible return-to-work permits based on immune status8 and, eventually, to achieve herd immunity.
Herd immunity is a form of indirect protection from SARS-CoV-2, that occurs when a large percentage of the population has become immune, whether through previous infection or vaccination. The hope, which has yet to be proven, is that the immune response in the majority of the immunized population will be strong enough to prevent further transmission of the virus. The herd immunity calculation suggests that at least 60% of the population should have protective immunity to stop transmission.
When we are infected with SARS-CoV-2, it typically takes 1-2 weeks to develop a response against the virus. SARS-CoV-2 enters lung cells by binding the ACE2 receptor expressed by the lung cells with its surface spike proteins. The body then responds with antibody producing B cells, where the antibodies specifically bind to the virus, preventing it from infecting cells, also called neutralizing antibodies. After around a week they start increasing in the blood9. The body also activates T-cells that recognize and eliminate other cells infected with the virus.
This combined response may clear the virus from the body, and if the response is strong enough, may prevent re-infection by the same virus as the B and T cells remembers the infection and can respond faster upon re-infection. Importantly, the antibodies persist in the blood for a long time after the infection and the neutralizing ability of these antibodies is a measure of how well they inhibit virus replication, and thus, how well we respond to a second infection and the extend of spreading to others.
Some governments have suggested that the detection of antibodies to the SARS-CoV-2, could serve as the basis for an “immunity passport” that would enable individuals to travel or to return to work assuming that the antibodies can protect against re-infection10.
What do we actually know about protective immunity after a SARS-CoV-2 infection?
Will we be protected if we are re-infected at a later time and will it prevent transmission to others? Much of our understanding of long-term coronavirus immunity obviously comes from SARS or MERS and not COVID-19 since it’s been around for such a short time. Measurements of antibodies in the blood of people who have survived those infections suggest that these defenses persist for some time: two years for SARS11, according to one study, and almost three years for MERS12, according to another study. However, the neutralizing ability of these antibodies was already declining during the study periods. These studies form the basis for a guess of what might happen with Covid-19 patients. After being infected with SARS-CoV-2, most individuals will have an immune response, some better than others. That response, it can be assumed, will offer some protection at least a year and then its effectiveness might decline.
Importantly, many in the medical community are closely watching the development of antibody drugs that could act to neutralize the virus, either once someone is already sick or as a way of blocking the infection in the first place. Several hospitals are also administering plasma from recovered patients to people who are sick with Covid-19, in the hopes that the antibodies of survivors will give the patients a boost13.
What about a vaccine that can prevent COVID-19?
Since it will be nearly impossible and extremely risky to eradicate the virus simultaneously, all around the world, by achieving herd immunity from a natural infection, our best chance to keep it in check is to develop vaccines that can prevent COVID-19.
The ideal vaccine would be safe, easy to administer, cheap and fast to manufacture on a big scale, and provide long-term protection against COVID-19 after just one administration. This protection would, hopefully, completely prevent infection with SARS-CoV-2. However, to begin with, we would be satisfied with a vaccine that could reduce the amount of virus generated during a typical infection. If an infected person is making less virus then they are less likely to spread it to others and less virus could also reduce the amount of damage caused by an infection in the patient.
What is the latest status of COVID-19 candidate vaccines?
Vaccine development is a long process involving both pre-clinical (animal) and clinical (human) testing to evaluate the safety and immunogenicity of the vaccine (how well the vaccine stimulates the immune system). It usually takes 10-15 years to have a licensed vaccine on the marked.
Vaccine development requires millions of dollars in funding, persuading regulators to approve human tests, demonstrating a vaccine’s safety, and obviously proving its effectiveness in protecting people from the pathogen. When I worked at Statens Serum Institute with the development of a new Chlamydia vaccine, it took 10 years before the vaccine was ready to be tested in a first clinical trial.
In stark contrast, experts have estimated a vaccine preventing COVID-19 may take only 12-18 months to develop. A huge international infrastructure is mobilizing to develop a vaccine at an unprecedented speed. In particular, the WHO Solidarity Trial are working to accelerate the vaccine development by harnessing a broad global coalition and coordinating clinical trials across the world 14. As of April 30th, eight candidate COVID-19 vaccines are being tested in humans and 94 are being evaluated in animals5.
The candidate vaccines use various vaccine designs[2] and many use the SARS-CoV-2 spike protein as vaccine target. We know from studies on SARS-CoV-1 and MERS-CoV vaccines that the spike protein on the surface of SARS-CoV-2 is an ideal target for antibodies15. Antibodies binding to the spike can interfere with virus binding to the cell, thereby neutralizing the virus which prevent infection.
The diverse vaccine design differs in how strong they stimulate our immune system and which parts of the immune system that are being mobilized. This will have an impact on how many vaccine boosts are needed, how well you are protected from the infection, and for how long. Importantly, the different vaccine platforms also vary in their capacity for rapid development and potential for big scale manufacturing at low-costs.
Today, ChAdOx1 nCoV-19 is considered one of the most promising COVID-19 vaccines candidates
Now, back to that vaccine my students and I got a sneak peek of at Oxford on Study Tour back in February. When we visited Professor Sarah Gilbert’s lab, we learned that on January 10, 2020, Sarah Gilbert and her vaccine group together with other scientists at the institute started working on the new ChAdOx1 nCoV-19 vaccine. The vaccine candidate is based on a chimpanzee adenovirus (a harmless cold virus) vector, named ChAdOx1, originally developed at the Jenner Institute, but now engineered to encode the SARS-CoV-2 spike protein. This vaccine technology has already been shown to generate a strong immune response from one dose inducing both B and T cell responses16 It is not a replicating virus, so it cannot cause an ongoing infection in the vaccinated individual. This also makes it safer to give the elderly and anyone with a pre-existing condition such as diabetes.
The vaccine team has previously performed human trials of similar vaccines for Ebola, MERS, and malaria and because of safety data from these trials, the British regulators has allowed unusually accelerated trials with the ChAdOx1 nCoV-19 vaccine.
Oxford’s Institute is one of the largest academic centers dedicated to non-profit vaccine research, with its own pilot manufacturing facility capable of producing a batch of up to 1,000 vaccine doses. Only last week, the institute began a Phase I clinical trial involving 1,100 people. At the same time as conducting the first clinical trial, production of the vaccine is being scaled up ready for larger trials, and potentially, future deployment. In May, the vaccine team will begin a combined Phase II and Phase III trial involving another 5,000 people.
It’s feasible that efficacy data from the Phase III trial could be generated by autumn 2020, in parallel with the achievement of large-scale manufacturing capacity, if everything goes as planned. The first few million doses of their vaccine could be available by September — at least several months ahead of any of the other announced efforts. However, these best-case timeframes are highly ambitious and their ability to determine vaccine efficacy will be affected by the amount of virus transmission in the local population over the summer16.
Donors are currently spending tens of millions of dollars to start the manufacturing process at facilities in Britain and the Netherlands even before the vaccine is proven to work. Other scientists involved in the project are working with a half dozen other drug manufacturing companies across Europe and Asia to prepare to roll out billions of doses as quickly as possible if the vaccine is approved. One is the giant Serum Institute of India, the world’s largest supplier of vaccines. Importantly, none have been granted exclusive marketing rights!
As professor Adrian Hill at the institute stated: “Vaccines are good for pandemics, and pandemics are good for vaccines.”
Jeanette is a DIS Copenhagen faculty member. She teaches courses in immunology and biotechnology. Jeanette got her PhD in Immunology at University of Copenhagen. She was a Senior Scientist at the Immune Targeting Group in Copenhagen and a Senior Scientist at the Department of Infectious Disease Immunology, Statens Serum Institute, Copenhagen. She has been with DIS since fall 2016.
Explore Jeanette’s Courses
>> Immunology
>> Medical Biotechnology and Drug Development
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Footnotes:
1. NIH; National Institue of Health. Coronaviruses. Corona viruses https://www.niaid.nih.gov/diseases-conditions/coronaviruses (2020).
2. Lisa Lockerd Maragakis, M.D., M. P. H. Coronavirus Disease 2019 vs. the Flu. Johns Hopkins Medicine
3. Mills, C. E., Robins, J. M. & Lipsitch, M. Transmissibility of 1918 pandemic influenza. Nature (2004) doi:10.1038/nature03063.
4. Administration, F. T. F. and D. Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment. (2020).
5. WHO; World Health Organization. Draft landscape of COVID 19 candidate vaccines. (2020).
6. Administration, F. T. F. and D. Coronavirus Treatment Acceleration Program (CTAP). (2020).
7. WHO; World Health Organization. “Solidarity” clinical trial for COVID-19 treatments. “Solidarity” clinical trial for COVID-19 treatments (2020).
8. Daniel M Altmann, Daniel C Douek, R. J. B. What policy makers need to know about COVID-19 protective immunity. Lancet 1–3 (2020) doi:DOI:https://doi.org/10.1016/S0140-6736(20)30985-5.
9. di Mauro Gabriella, Cristina, S., Concetta, R., Francesco, R. & Annalisa, C. SARS-Cov-2 infection: Response of human immune system and possible implications for the rapid test and treatment. Int. Immunopharmacol. (2020) doi:10.1016/j.intimp.2020.106519.
10. WHO; World Health Organization. Critical preparedness, readiness and response actions for COVID-19. Critical preparedness, readiness and response actions for COVID-19 (2020).
11. Mo, H. et al. Longitudinal profile of antibodies against SARS-coronavirus in SARS patients and their clinical significance. Respirology (2006) doi:10.1111/j.1440-1843.2006.00783.x.
12. Payne, D. C. et al. Persistence of antibodies against middle east respiratory syndrome coronavirus. Emerg. Infect. Dis. (2016) doi:10.3201/eid2210.160706.
13. Times, T. N. Y. Blood Plasma From Survivors Will Be Given to Coronavirus Patients. (2020).
14. WHO; World Health Organization. WHO Solidarity Trial – Accelerating a safe and effective COVID-19 vaccine. (2020)
15. Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (80-. ). (2020) doi:10.1126/science.aax0902.
16. Lane, R. Sarah Gilbert: carving a path towards a COVID-19 vaccine. Lancet (2020) doi:10.1016/S0140-6736(20)30796-0.
[1] Note that influenza has another mechanism where it can re-assort the viral genomes with various influenza strains which also result in genome variability
[2] The varies candidate vaccine design include live-attenuated or inactivated SARS-Cov-2 virus, subunit vaccines using the SARS-CoV-2 spike protein as vaccine target, or RNA and DNA vaccines encoding the spike protein.