All the important information summarzied here courtesy of MCW Peds Resident:
Dr. Swathi Prasad.
Since its outbreak in the end of 2019 and spread to pandemic status by early 2020, SARS-CoV-2, the causal coronavirus of COVID-19, has infected more than 3.4 million individuals worldwide (as of 5/2 per the Hopkins COVID-19 tracker). Initial responses included public health measures, but now the focus has begun to shift to therapeutic interventions and prevention via vaccine development. While previous timelines for vaccines have been close to 10 years from inception through all trials and assessments by regulatory agencies and eventual mass manufacturing and distribution, the Ebola pandemic cut this timeline in half, and companies are hoping to reduce the time needed for a COVID-19 vaccine to one year. Below is a summary of some vaccine basics, some of the more advanced trials, and a myriad of sources as the landscape of vaccine development continues to change.
A quick disclaimer: Even as I write this article, the world continues to be updated with both more information about COVID-19 as well as information from the ongoing trials. One of the most comprehensive and updated resources continues to be the “World Health Organization’s landscape of COVID-19 candidate vaccines” with list here (updated as of 04/30/20), which can also be found by googling “WHO draft landscape of COVID-19 candidate vaccines”.
Coronavirus is…
…a betacoronavirus (described as such by the “crown” of spikes or surface glycoproteins under electron microscope), with genomic sequencing similar to that of 2003’s SARS virus. This RNA genome appears to encode in particular for a spike protein (S protein) that allows it attack our bodies by attaching to the angiotensin-converting enzyme 2 (ACE2) receptor, leading to uptake into our cells. With a significant number of severe infections and mortality rate, health experts around the globe recognize the need for focus not only on therapeutics but also on vaccines for this new virus.
Vaccines are…
…important, and in this blog, we shouldn’t have to explain why. Vaccine technology over the last decade has led to the development of RNA and DNA candidates, vector vaccines, protein vaccines, and a few other mechanisms or platforms (see below). As of now, we know that SARS-CoV-1 and MERS-CoV vaccines showed that the S protein on the surface of the virus is an ideal target for a vaccine by allowing antibodies to target this pike and interfere with binding to ACE2 receptors (see Figure 1), neutralizing the virus, making this a potential starting point for some of the current vaccine developers.
Why do we think a vaccine might work for COVID-19?
SARS-CoV-2 doesn’t appear to be “formidable” – it changes slowly which is important in developing a vaccine that will be universally impactful, and vaccines against related coronaviruses causing SARS and MERS have worked well in animal models. For example, the SARS-CoV-1 vaccine model did show protection in animal models challenged with that virus, but also some complications including eosinophilic infiltration in the lungs, liver damage in ferrets. However, studies as development persisted all correlated vaccination with greater survival, reduced virus titers, and/or less morbidity compared with unvaccinated animals. While vaccine researchers continue to work towards a vaccine, they acknowledge the risks associated with them, thus leading to very strictly defined and closely regulated trials before anything will be distributed to the public.
But there are still a few unknowns about the coronavirus that will also impact vaccine development…
The four human coronaviruses that cause minor colds don’t trigger long-lasting immunity, leading to a consideration of whether there is a waning antibody response. As a whole, we are still trying to figure out what re-infections look like, and their time frame, which requires more testing. For now, vaccine developers will need to take the potential for waning humoral immunity in months or years into consideration, especially as countries consider how to wean down restrictions on physical distancing.
Other important factors include our knowledge of the worse impact this infection has on older individuals, in particular due to this segment of the population responding less well to vaccines. While they may benefit if vaccination prevents transmission in younger adults, the need for more antigen or adjuvants for vaccinations for this population should be considered.
So, what’s out there right now? (as of April 23, 2020)
- Recommended reads:
- The COVID-19 vaccine development landscape, on Nature (April 9, 2020)
- Covid-19 Vaccine Frontrunners, on The Scientist (updated April 23, 2020)
- COVID-19 Vaccine Candidates, on AssayGenie (last updated date unknown)
Current vaccine proposed mechanisms
(The following table was adapted from Table 1 of a status report published in Immunity. )
| Platform | Target and Mechanism | Existing, Licensed Human Vaccines Using the Same Platform | Advantages | Disadvantages | Current COVID-19 vaccine in progress at the clinical evaluation level? |
| RNA vaccine (additional source) | Targets the S protein Introduces an mRNA sequence coded for a specific antigen (the S protein) to teach the immune system to recognize and fight it | No | Faster to produce Cheaper to produce Safer to patient, and when being handled due to no infectious virus presence Generally show good tolerance by healthy individuals | Safety issues with reactogenicity have been reported – the mRNA strand can elicit unintended reactions Delivery is challenging as mRNA is quickly broken down. | Yes 1. Moderna |
| DNA vaccine (additional source) | Targets the S protein Introduces plasmid containing DNA sequence encoding an antigen (the S protein) to stimulate B- and T-cell responses | No | No infectious virus needs to be handled Easy scale up Low production costs High heat stability Tested in humans for SARS-CoV-1, rapid production possible DNA and mRNA offer flexibility in terms of antigen manipulation and potential for speed | Vaccine needs specific delivery devices to reach good immunogenicity | Yes 1. Inovio Pharmaceuticals |
| Inactivated Virus (additional source) | Targets the whole virion Bacteria or virus are grown in culture, then inactivated with heat/chemicals, purified to vaccine components only, and then administered via injection. | Yes – polio, hep A | Proven and straight forward process used for several licensed humanVaccines, and thus existing infrastructure can be used Has been tested in humans for SARS-CoV-1, adjuvants can be used to increase immunogenicity (see below) | Large amounts of infectious virus need to be handled (could be mitigated by using an attenuated seed virus). Antigen and/or epitope integrity needs to be confirmed. Requires multiple doses (first dose “primes”, the next confer protection), and antibody titers can wane over time with a mostly humoral response. | Yes 1. Beijing Institute of Biological Products/Wuhan Institute of Biological Products 2. Sinovac |
| Non-replicating viral vector (additional source) | Targets the S protein Use an inactivated or killed viral vector (such as adenovirus) to express proteins of the virus to be recognized by the immune response and create a response | Yes – VSV | No infectious virus needs to be handled Excellent preclinical and clinical data for many emerging viruses, including MERS-CoV Viral vectors offer high level of protein expression, long term stability, induce strong immune responses | Vector immunity might negatively affect vaccine effectiveness (depending on the vector chosen). | Yes 1. University of Oxford 2. CanSino and Beijing Institute of Biotechnology |
| Recombinant protein vaccines (additional source) | Targets the S protein Virus-like particles (often those from the outer shell of a virus) are used to prompt an immune response, but ar non-infectious as they do not contain genetic material. | Yes – influenza, HPV, HBV | No infectious virus needs to be handled, adjuvants can be used to increase immunogenicity. Already licensed vaccines are based on recombinant proteins, and so could take advantage of existing large-scale production capacity | Global production capacity might be limited Antigen and/or epitope integrity needs to be confirmed. Yields need to be high enough. | |
| Live attenuated vaccines (additional source) | Targets the whole virion Derived from wild or disease-causing viruses (or bacteria), weakened in a lab by epeat culturing, and then dosed in tiny amounts to the body to stimulate an immune response. | Yes – MMR, varicella | Straightforward process usedfor several licensed humanvaccines, existing infrastructurecan be used. Often confer immunity with one dose. | Creating infectious clones for attenuated coronavirus vaccine seeds takes time because of large genome size. Safety testing will need to be extensive. | |
| Adjuvants (source) | Improve immune response and increase efficacy of vaccines which may have weak immunogenicity | Could enhance immunogenicity and make lower doses viable, enabling vaccination of more people without compromising protection | Multiple developers have indicated plans to develop adjuvanted vaccines against COVID to us with vaccines developed by others |
Why do we need to consider so many platforms?
We assume that protection will come from the activation of and presence of neutralizing antibodies against the viral spike S protein, preventing uptake by human ACE2 recptor, though some propose that instead a T cell response may be a better correlate based on some existing monkey studies. Diverse platforms, not all of which are the basis for licensed vaccines, may allow for increased speed of development and manufacture, and may be better suited for specific population subtypes.
Ok, fine. But I’m really here for an update on who has ACTUALLY got a vaccine going.
Recommended reading, updated 4/23: COVID-19 Vaccine Frontrunners via The Scientist
Moderna, CanSino, and the first human trials (source)
Moderna’s experimental vaccine first came to fame when the first US citizen received their mRNA vaccine on 3/16 in the first US launch of a clinical trial against COVID-19. (On this same date, China’s CanSino vaccine trial began their own trial.) These were the first two to go to human trials. This happened relatively quickly – Chinese researchers first publicized the full RNA sequence on 1/10/20, and less than ten weeks later, a vaccine was administered to volunteers in the Kaiser Permanente Washington Health Research Institute trial. Moderna’s vaccine is made of lipid nanoparticles containing mRNA that will direct cells to produce the spike protein previously described to train the body into an immune response.. Linked here is a link to their timeline and work, as well as FAQ. Notably, it was not tested in animals before going to human testing. It is currently in the phase I, open-label, dose ranging clinical trial stage with testing in males and non-pregnant females.
CanSino’s vaccine uses a non-replicating version of Adenovirus-5 (another common-cold-causer) as a vector to carry in the gene for the coronavirus spike protein. Possible limitations described have been that existing immunity may lead to a response against the vector itself, preventing the spike protein from even being delivered. Previous trials of an Ad5 based vaccine (against HIV, by Merck) also led to harm, but a 2017 Chinese produced Ebola vaccine showed a good safety profile, thus reducing concern for now. CanSino is now in phase I and phase II of clinical trials.
Sinovac (1)
As of 4/23/20, scientists in Sinovac Biotech reported that one of the vaccines in development had protected a rhesus macacques from infection by new coronavirus. The vaccine itself is a chemically inactivated version of the whole virus particles added to an immune booster called alum (the same strategy used for a SARS vaccine previously developed), and was introduced to eight monkeys; three weeks later, the monkeys had SARS-CoV-2 introduced via tubes down the tracheas. Seven days after virus introduction, it was undetectable in pharynx or lungs. The control animals showed high levels of viral RNA in several body parts and severe pneumonia.
Feedback thus far has been mixed. Some experts are in favor of this “old school” method, which would be appropriate to make and distribute in lower-middle-income countries. Others are concerned that this number is too small for statistically significant results (and that the method of introduction of virus does not reflect the process of human infection). Most notably, the monkeys don’t seem to develop the full range of severity of symptoms seen in humans.
Phase I clinical trials were started recently in Shanghai with plans for high and low doses and a placebo to be given to an equal distribution of 144 volunteers. Sinovac has their own information here.
Inovio Pharmaceuticals (1, 2)
Inovio seems to have already been working on a DNA platform, and leveraged this to create their own COVID-19 vaccine candidate. After mice and guinea pigs mounted immune esponses against the virus, they moved to monkeys. Now in Phase I trial in Pennsylvania and Kansas City, the plan is for a two dose vaccine four weeks apart after preclinical animal model testing with encouraging immune response data (per company).
University of Oxford (1, 2, 3)
Within the last few days, Oxford began their own Phase I/II trial using the same adenovirus (non-replicating) vector from chimpanzees used to target MERS in Saudi Arabia. As of 4/27, new updates were reported that six rhesus macaque monkeys dosed with the vaccine last month and then exposed to heavy virus quantities were healthy more than 28 days later. This particular trial is prioritizing recruitment of healthcare workers given higher likelihood of exposure, and now with their vaccine results from monkeys as well as previous trials (including one from 2019 against an earlier coronavirus) have allowed this team to hope to test 6,000 people by end of May, and potential have their vaccine ready by the end of October with emergency approval.
Beijing Institute of Biological Products (1)
Based out of WuHan, this company has also been working on phase I/II clinical trials for an inactivated COVID-19 vaccine. Less information was easily found on this product from more objective sources, but the clinical trial information page itself is notable for its proceeding after studies in monkeys, mice, rabbits, and guinea pigs supported its movement to testing in humans, and for its inclusion criteria of healthy subjects from age 6 upwards.
Who is funding all of these efforts?
For one, the Coalition for Epidemic Preparedness Innovations (CEPI), a nonprofit set up to coordinate R+D for vaccines against emerging infectious diseases. They have been investing in manufacturing facilities, as well as staging clinical trials for eight total groups in the hopes that they can compress the overall timeline. Their goal? To push six of eight products into safety studies, with the hope that three will be worthy of full-scale trials. So far, they have nearly $30 million invested.
Another source of funds has been the Biomedical Advanced Research and Development Authority (BARDA), part of the HHS, which has sponsored in particular the Johnson&Johnson Janssen division, Moderna’s efforts, and Sanofi’s new recombinant vaccine candidate.
How long will we have to wait?
We’ve all heard Dr. Anthony Fauci predict that a vaccine may take over a year and up to two years (optimistically) to get to the public, especially if we stick to the regulations in place for safety purposes (animal models, testing toxicity and safety, phase I/II/III trials), but also as we try and figure out what manufacturing may look like. With no previous coronaviruses, we’re not only creating the vaccine but production platforms, vectors, distribution networks in parallel in the hopes of cutting down on time to giving this out to the general population. Some companies hope to launch efficacy trials by the end of 2020, to determine by the beginning of 2021 whether a vaccine works. China’s companies think they may be able to move things up sooner.
All companies and experts acknowledge that the vaccines might be too late for the first wave of this pandemic, but might be useful for additional waves, or in a post-pandemic scenario as the virus continues to circulate. Viruses keep coming, and other viruses will have their own waves this coming fall. Development even during this pandemic will be important to our management of future outbreak infectious diseases.
Thank you Dr. Swathi Prasad for this great summary!
Where did we find all this info? See our sources with their links below!
- Regulatory Affairs Professional Society
- Healthline
- NIH/NIAID
- FDA COVID Treatment Acceleration Program
- Nature
- World Health Organization
- https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
- https://www.who.int/emergencies/diseases/novel-coronavirus-2019
- R+D blueprint and latest reports (including constantly updated landscape of COVID vaccines
- Public statement for collaboration on COVID-19 vaccine development
- R+D Blueprint for An international randomized trial of candidate vaccines against COVID-19
- Science
- Cell
- CDC “Principles of Vaccination”
COVID-19 RESOURCE SITE FOR PEDS CRITICAL CARE AT MCW 