According to the WHO, there are 24 COVID-19 vaccines in human clinical trials (the NY Times lists 27) and another 142 candidate vaccines in preclinical evaluation. Many of these vaccine trials started in March/April of this year and early positive results are being reported. A few of the vaccines have advanced to phase 3 trials; a few others will enter phase 3 in the next week or two.
Here we take a look at some of the leading vaccine candidates. All of these vaccines have shown the ability to stimulate the human immune system to generate antibodies and are relatively safe for humans, although not without minor adverse effects. Most vaccines required two doses to produce good results.
But first, let’s get a high level understanding of what these clinical trial phases mean and the sorts of answers they provide on the road to vaccine approval.
Vaccine Clinical Trials and Phases
Preclinical: Tests are conducted in-vitro and in animals to check for anti-viral properties and safety.
Phase 1: The vaccine is given to a small number of volunteers, primarily to check for safety of the vaccine in humans and to measure the immune system response. Multiple dosage levels are tested to evaluate the dose that gives the right balance between low adverse effects and proper immune response. Participants tend to be healthy adults.
Phase 2: Similar to phase 1 but with a larger number of volunteers, including children and the elderly. Phase 2 may be started after preliminary results from phase 1 to shorten the testing schedule. The presence of antibodies is quantified and compared to that in infected patients. Note that -
- Typically, antibody levels decline over time but B and T cells get primed for future antibody production; most of the trials have measured the latter too.
- For COVID-19, these trials have lasted about 3 months, so they do not show results for longer times, but that does not imply that immunity will disappear after 3 months.
Phase 3: In this phase, scientists learn whether the vaccine actually protects against the virus. This phase requires a large number of volunteers (thousands to tens of thousand) and an extended testing period. The vaccine is administered to a large set of volunteers; a somewhat smaller group acts as a control group, whose members are given a placebo. Individuals are not aware of who got what. Participants go about living their normal lives. Scientists periodically measure how many individuals in each group catch the infection and develop symptoms. The fraction of the placebo group that get infected and develop symptoms vs the fraction of the vaccinated group that get infected but do not develop symptoms, provides a measure of the efficacy of the vaccine. A certain minimum fraction of each group needs to get infected for results to be statistically significant. Asymptomatic infections create some challenges in measuring these metrics.
How long does phase 3 have to last? Typically it lasts for years since scientists are interested in finding out how effective the vaccine is over different periods of time ranging from months to years. Early results can be obtained if there is a relatively high rate of infection among the regional population; hence, trials tend to be done in regions where the virus is spreading fast. In the case of COVID-19, tests are being done in the US, South Africa, Brazil UAE and Bangladesh. Results may become available within 3 months, but these results would not predict the efficacy of the vaccine at the 6-month or 12-month mark. So, phase 3 trials will probably continue beyond 3 months, but the preliminary results may guide decisions on whether the vaccine can be approved for emergency use.
Formal approval for use in the general population will require longer periods of testing, but approval for emergency use among vulnerable members of society, such as health workers, may be granted sooner.
Note that vaccine trials are quite different and more challenging than therapeutic drug trials. With drugs, you can seek participants who have the disease and test out the drug on them along with a control group that is given placebos. Results can be generated in months. With vaccines, you are dealing with healthy participants and waiting for them to get infected naturally. You cannot infect them intentionally to measure the efficacy of the vaccine.
There are conversations about challenge trials, where volunteers are deliberately exposed to the vaccine to speed up evaluation. Nothing definitive yet, since major ethical and legal challenges need to be sorted out.
A Synopsis of the leading vaccine candidates
The following table shows the major vaccine efforts organized by vaccine type and country. Note that there are many more vaccines in clinical trails than the subset shown below.
Country |
Genetic (mRNA, DNA) |
Viral vector |
Protein based |
WhOle Virus |
USA |
Moderna (3)
Innovio (2)
|
J&J+IDMC (pre)
Merck+IAVI (pre)
|
Novavax (2) |
|
Europe |
Pfizer+BioNTech (3)
Imperial College+
Morningside (1)
Curevac (1)
|
University of Oxford + AstraZeneca (3)
|
|
|
China |
People's Liberation Army (PLA) Academy of Military Sciences/Walvax Biotech (1) |
CanSino (2)
|
Clover Biopharm (1)
|
Sinovac (3)
Sinopharm (3)
Institute of Medical Biology (2)
|
Russia |
|
Gamaleya Research Institute (2) |
|
|
Notes
- Note that the table has 5 columns. Scroll right if necessary.
- Clinical trial phase is indicated in parenthesis.
- Companies funded by the U.S. Warp Speed program are indicated in bold.
- Some of the phase 3 trials have not started but are scheduled to begin shortly.
- The US seems to be focused on the more modern RNA and viral vector based vaccines, while China has a broader range with emphasis on traditional virus based vaccines.
- Most organizations are overlapping trial phases to compress the schedule.
Vaccine Technologies
The following is a short synopsis of the major vaccine technologies being pursued by different groups and referred to in the above table.
- Genetic Vaccine — These experimental vaccines use engineered genetic material (RNA or DNA), which causes the immune system to generate antibodies. These vaccines do not contain virus segments and can be potentially developed more quickly and easily than other vaccines. No RNA vaccines have been approved for human use yet.
- Viral vector — This involves putting a gene for a viral protein into a different virus (one that will not cause illness but can replicate). Replication of the viral vector also produces copies of the viral protein, which triggers an immune response to that protein.
- Protein based — These vaccines use a coronavirus protein or a protein fragment to provoke an immune response.
- Whole Virus — These vaccines use a weakened or inactivated version of the COVID-19 virus to generate an immune response.
In the News:
Moderna
Moderna released their preliminary report in the NEJM on Monday, July 14.
The researchers measured high levels of neutralizing antibody activity against the coronavirus; levels were above the average levels observed in serum taken from people with confirmed COVID-19 infection.
The trial, which was broadened in April to include participants older than 55 years, now has 120 enrollees, but the preliminary report included only the 18- to 55-year-old group.
Phase 3 trials with 30,000 participants is scheduled to start on July 27.
Oxford
The Oxford vaccine group released their report in the Lancet on Monday, July 20.
The trial showed that participants developed a healthy level of antibodies as well as T cells, with mild to moderate side effects.
British-Swedish pharmaceutical giant AstraZeneca has lined up agreements to produce 2 billion doses. AstraZeneca has agreed to sell the vaccine on a not-for-profit basis during the crisis.
The technical name of the vaccine is ChAdOx1 nCoV-19, as it is made from a virus called ChAdOx1, which is a weakened and non-replicating version of a common cold virus (adenovirus) found in chimpanzees. The vaccine has been engineered to express the SARS-CoV-2 spike protein.
The vaccine is currently on trial in the UK, where over 4,000 participants are already enrolled into the clinical trial and enrollment of an additional 10, 000 participants is planned. Trials in South Africa and Brazil were started earlier this month. The phase 3 trial in Brazil began on June 28 and will enroll 5,000 in Sao Paulo, Rio de Janeiro and a site in the Northeast of Brazil. There will be a large trial involving 30,000 people in the US as well.
Pfizer/BionTech
Pfizer/BionTech posted preliminary results from their Phase 1/2 trials in the United States and Germany earlier this month.
Results were similar to those of Moderna. Antibody and T cell generation were observed in 45 volunteers.
Phase 3 trials are expected to start in August with up to 30,000 participants.
CanSino
The phase 2 trial for this vaccine showed antibody and T cell response, but neutralizing antibodies were observed in only 59% of participants. Only a single dose was tested.
The vaccine uses a weakened human cold virus called an adenovirus to deliver genetic material mimicking coronavirus. It is possible that for people who have been infected by that adenovirus in the past, the immune system does not generate a strong response. Compared to younger people in the study, older participants had a significantly lower immune response and tolerated the vaccine better. Further research is needed to evaluate whether booster doses could help in such cases.
In an unprecedented move, the Chinese military approved the CanSino vaccine on June 25 for a year for use by its soldiers.
CanSino is in talks with Russia, Brazil, Chile and Saudi Arabia to launch the Phase 3 trial. www.reuters.com/...
Sinovac
Chinese company Sinovac Biotech launched a phase 3 trial of its inactivated virus vaccine in Brazil this month. Another trial is planned in densely populated Bangladesh. www.reuters.com/…
SinoPharm
State-owned Chinese company Sinopharm launched Phase 3 trials of its inactivated virus vaccine this month in the United Arab Emirates. Abu Dhabi’s health minister was the first volunteer to be injected, and 15,000 people were scheduled to participate in total.
Operation Warp Speed
The U.S. government’s Operation Warp Speed (OWS) program is a public–private partnership, to facilitate and accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics. It has (unofficially) selected five vaccine projects to receive billions of dollars in federal funding to accelerate development and production. Its stated goal is to “deliver 300 million of doses to the American people by the end of the year.” and more next year. The program is investing (with tax-payer dollars) in the development and production the vaccines and supporting equipment (e.g., vials and syringes).
Congress has directed almost $10 billion to this effort through supplemental funding, including the CARES Act; more than $6.5 billion is designated for countermeasure development through BARDA and $3 billion for NIH research.
It is a worthy initiative no doubt, but given the infectious incompetence and political nature of administration, there is justifiable suspicion that the program’s lack of transparency and its schedule are designed to boost trump’s political fortunes, rather than COVID-19 immunity in the American people.
The HHS website even claims that AstraZeneca will make available at least 300 million doses of a coronavirus vaccine called AZD1222, with the first doses delivered as early as October 2020. The is no website per se for OWS, it is just a handful of news releases.
I could find any info on pricing, although the news release about Pfizer mentioned that “the vaccine would be available to the American people at no cost. As is customary with government-purchased vaccines, healthcare professionals could charge insurers for the cost of administering the vaccine.”
Organization |
OWS Funding |
Doses in Initial Contract |
Links |
Moderna |
$483 million |
|
www.hhs.gov/... |
University of Oxford + AstraZeneca |
Up to $1.2 billion |
300M |
www.hhs.gov/... |
Pfizer+BioNTech |
$1.95 billion |
100M |
www.hhs.gov/... |
J&J+Beth Israel Deaconess Medical Center
|
$456 million |
|
link
|
Merck+IAVI |
? |
|
|
Novavax |
Up to $1.6 billion promised |
100M |
link
|
Epilogue
The development of vaccines (and treatments) for COVID-19 is progressing at unprecedented speed. What used to take years is now expected to take 12-18 months. How is that possible? Modern vaccine technology is far more advanced that what we had 80 years ago, even 10 years ago. Our understanding of immunology and the genetic basis of viruses and the human body means that we can engineer vaccines and treatments far more precisely and rapidly then ever before. The amount of brainpower focused on COVID-19 is astronomical. Phase 1 and 2 results are encouraging, more so because multiple vaccines have given similar results. Plus there is the urgency to develop a vaccine and traditional testing methods are being adapted for speedier trials.
For those who feel that we do not know enough about COVID-19 and hence a vaccine is unlikely, please keep in mind that not knowing everything does not imply that we know nothing. Let’s remind ourselves that thousands of virologists, immunologists and scientists around the world understand this far better than any of us amateur virologists. Let’s keep ourselves informed from reliable sources and let our thinking be driven by the sum total of the information our there, not anecdotal stories or deliberate misinformation from the Internet. As someone famously said, listen to the experts, not to stupid.
There are no guarantees that any vaccine will succeed, but I would not bet the farm on a prediction that there will be no vaccine. Perhaps, the immunity may be short-lived, perhaps it will require periodic booster shots, but one or more are likely to work and help stop the spread of the virus. If the virus mutates, vaccines can be adapted. Besides the major vaccine efforts mentioned here, there are scores of others, and research will continue on many of them in search of a better vaccine.
As for timing, preliminary results will probably be available in 3-6 months. Whether positive results will be sufficient to approve a vaccine for limited use or for widespread use is a call that scientists (and unfortunately politicians) will have to make.
What if an effective vaccine does not emerge? What’s plan B? Here is an article that explores the question.
Further Reading
- An mRNA Vaccine against SARS-CoV-2 — Preliminary Report (Moderna) — www.nejm.org/…
- Hopeful results from phase 1 Moderna COVID vaccine trial — www.cidrap.umn.edu/…
- Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial (Oxford) — www.thelancet.com/…
- Studies provide glimpse at efficacy of Covid-19 vaccines from Oxford-AstraZeneca and CanSino — www.statnews.com/...
- Covid Vaccine Front-Runner Is Months Ahead of Her Competition (Oxford)— www.bloomberg.com/…
- Phase 1/2 Study to Describe the Safety and Immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in Adults 18 to 55 Years of Age: Interim Report (BioNTech vaccine) — www.medrxiv.org/…
- Pfizer CEO Albert Bourla Raises Expectations That the Pharmaceutical Giant Can Deliver a COVID-19 Vaccine by Fall — time.com/…
- Immunogenicity and safety of a recombinant adenovirustype-5-vectored COVID-19 vaccine in healthy adults aged18 years or older: a randomised, double-blind, placebocontrolled, phase 2 trial (CanSino) — www.thelancet.com/...
- World's 1st inactivated COVID-19 vaccine produces antibodies (Sinopharm)— www.prnewswire.com/…
- Russia to mass produce experimental COVID-19 vaccine: wealth fund head — www.reuters.com/…
- In Coronavirus Vaccine Race, China Strays From the Official Paths — www.nytimes.com/…
- What happens next, as coronavirus vaccine trials move to a new phase? — www.scmp.com/…
- Coronavirus vaccines get a biotech boost — www.nature.com/…
- Operation Warp Speed — en.wikipedia.org/...
- Coronavirus Vaccine Tracker — www.nytimes.com/…
- COVID-19 TREATMENT AND VACCINE TRACKER — covid-19tracker.milkeninstitute.org
- Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection (2016, not COVID-19) — www.sciencedirect.com/…
- Data Byte: comparing clinical data from five COVID-19 vaccines — www.biocentury.com/...
P.S. I do not have any expertise in biology or medicine, so hopefully those more knowledgeable here can correct any mistakes and contribute additional insights.
Also, I had published this diary for a short time on Thursday, but I unpublished it since I had to step away. I also made some improvements to the diary since then.