Since the beginning of the pandemic, little has been met with more anticipation (or hesitancy) than the promise of a COVID-19 vaccine. However, by mid-November 2020, less than a year after SARS-CoV-2 gained global recognition as a public health threat, this “promise” has moved from speculation to possibility, and the news has everyone talking.
Southeast Asia is the source of 95 percent of global cassava exports, and the detection in 2015 in Cambodia of the potentially harvest-devastating Sri Lankan cassava mosaic virus (SLCMV) raised alarm. By 2016, the disease, which cannot always be detected visually, had spread, showing its potential to become a major threat to the livelihoods of millions of smallholder farming families.
COVID-19 has brought attention back to deadly viruses. Meet hard-working scientists in Singapore and elsewhere racing to identify emerging pathogens, battle existing viruses and co-operate to find urgently-needed treatments and vaccines.
Since the beginning of the pandemic, little has been met with more anticipation (or hesitancy) than the promise of a COVID-19 vaccine. However, by mid-November 2020, less than a year after SARS-CoV-2 gained global recognition as a public health threat, this “promise” has moved from speculation to possibility, and the news has everyone talking. In the past month, 2 major pharmaceutical and biotech companies, Pfizer (in partnership with BioNTech) and Moderna, Inc., have announced tremendous, and unprecedented, success following the primary efficacy analyses of their Phase 3 COVID-19 vaccine trials. Not surprisingly, the Pfizer and Moderna vaccines are based on similar technology, which many are hoping will revolutionize vaccine science. Concurrently, there are 56 additional vaccines being tested in clinical trials, 13 of which are conducting Phase 3, large-scale efficacy studies in humans (as of Dec. 3, 2020).
Emerging data from these studies may represent the most pivotal advancements to date in the fight against COVID-19, but amidst all the buzz, many questions continue to circulate, making it more vital than ever that the general public, and scientists alike, have a thorough understanding of what goes into and is coming out of these trials. One thing is certain: the success or failure of any emerging vaccine will depend as much on earning public acceptance as it does Food and Drug Administration (FDA) approval.
How do the Moderna and Pfizer COVID-19 vaccines compare?
At the outset, the Pfizer and Moderna vaccines appear to be similar in structure and function. Both vaccines use mRNA platforms, a gene-based technology that has long been explored for its disease prevention and treatment potential but has generated little quantifiable success in the vaccine department, due primarily to engineering challenges...until now. Within a week’s time (Nov. 9-16, 2020), both companies reported their vaccine candidates to be more than 90% effective at preventing symptomatic COVID-19.
What do the data show?
Data from the Moderna Phase 1 and Pfizer Phase 1/2 trials have been published. However, at this time, the Phase 3 analyses of both trials have only been publicized as press releases, and the publication of complete study data is still pending.
Pfizer
90% efficacy was estimated following the interim analysis of Pfizer’s Phase 3 COVID-19 vaccine trial (Nov. 9, 2020). This mid-point analysis was based on 94 confirmed COVID-19 cases, 85 of which were observed in the placebo group, and 9 of which were observed in the vaccine group.
95% efficacy was reported after the final analysis of Pfizer’s Phase 3 COVID-19 vaccine trial (Nov. 18, 2020). The efficacy in adults 65+ years of age was determined to be over 94%, and 9/10 severe cases of COVID-19 were observed in the placebo group.
What that means: The final analysis was based on 170 confirmed cases of COVID-19. 162 of those were observed in the placebo group. That means only 8 people who received the Pfizer vaccine developed COVID-19 symptoms after being infected with the SARS-CoV-2 virus.
Moderna
94.5% efficacy was reported following the interim analysis of Moderna’s Phase 3 COVID-19 vaccine trial (Nov. 16, 2020). This mid-point analysis was based on 95 confirmed cases of COVID-19. 90 of those were observed in the placebo group, and 5 were observed in the vaccine group.
94.1% overall efficacy and 100% efficacy against severe disease were reported after the final analysis of Moderna’s Phase 3 COVID-19 vaccine trial (Nov. 30, 2020).
What that means: The final analysis was based on 196 cases of confirmed COVID-19. 185 of those were observed in the placebo group. That means only 11 people who received the Moderna vaccine developed COVID-19 symptoms after being infected with the SARS-CoV-2 virus. Furthermore, 30/30 severe cases were observed in the placebo group, meaning there were zero cases of severe COVID-19 disease in those who were vaccinated.
How were the studies conducted?
When a vaccine trial hits Phase 3, the product is being actively tested in large populations of humans. Both Pfizer’s and Moderna’s Phase 3 trials were randomized, observer blinded 1:1 placebo-controlled studies. Enrolled participants were randomly administered a predetermined dosage of vaccine (30 µg for Pfizer and 100 µg for Moderna) or a placebo saline injection, and the investigators and participants did not know who was assigned to each group.
These vaccines both rely on a 2-dose regimen that must be administered 3-4 weeks apart, and if protection is achieved, it occurs by 7 days after the second dose, or 28 days after initiation of vaccination. COVID-19 cases were therefore measured from 7 days after the second dose (of vaccine or placebo) was administered. At that point, if a patient developed symptoms of disease and tested positive for COVID-19, researchers turned to trial records to determine/reveal whether they had been given the vaccine or placebo.
150 clinical trial sites in 6 countries and 39 U.S. states.
42% of global and 30% of U.S. participants came from racially and ethnically diverse backgrounds. A further breakdown of these demographics was provided.
41% of global and 45% of U.S. participants aged 56-85.
37% of participants from communities of color, including more than 6,000 identifying as Hispanic or LatinX and more than 3,000 identifying as Black or African American.
42% of participants from medically high-risk groups (including individuals 65 years of age and older, as well as those with pre-existing/underlying chronic diseases, such as diabetes, severe obesity and cardiac disease).
Who is evaluating the data from these studies?
An independent Data and Safety Monitoring Board is in charge of evaluating the safety and efficacy of vaccine trials. These committees are composed of people who do not own the company or trials under review, which is important to help ensure that those who stand to profit from the vaccine are not involved in the evaluation of trial data.
How do mRNA vaccines work?
This type of vaccine depends on a nucleic acid courier known as messenger RNA (mRNA) to deliver targeted genetic messages to the protein-making machinery (ribosomes) of host cells. Both the Pfizer and Moderna vaccines deliver mRNA that encodes a prefusion stabilized form of the SARS-CoV-2 spike (S) protein. Vaccination initiates host production of spike protein copies, which in turn triggers the immune system to create antibodies in response to the foreign protein. Depiction of mRNA vaccine-induced antibody response against SARS-CoV-2 spike proteins.
Source: American Society for Microbiology
Is it possible for someone to contract COVID-19 from this vaccine?
No. Because mRNA vaccines use a synthetic message (the genetic code) of a single virus protein to generate an immune response, they cannot cause SARS-CoV-2 infection in vaccine recipients.
What are some of the benefits of mRNA vaccines?
Fast Production
mRNA vaccines are especially efficient to produce, a factor that has undoubtedly given this platform an advantage during the SARS-CoV-2 pandemic. The reason mRNA vaccines can be so quickly engineered is that they're almost entirely synthetic. All researchers really need is the genetic sequence of the desired protein (and a delivery platform). No live virus, culture, eggs or bioreactors required.
Within 2 months of learning the sequence of the SARS-CoV-2 spike protein, Moderna was able to engineer enough vaccine to begin its first human trials, but this speedy production was not rushed. Its important to understand that COVID-19 vaccines are dependent upon, and made possible by, nearly 17 years of research, which began when SARS-CoV was first identified in 2003, as well as decades of research and development surrounding mRNA technology.
Heightened Immune Response
Additionally, in comparison to other vaccine platforms, RNA appears to cause a heightened immune response that not only stimulates antibody production, but also induces T-cell activity. Interestingly, virus specific T-cells, lymphocytes that recognize and eliminate infected cells, have still been detected in cases of SARS-CoV-2 infection that do not appear to generate detectable antibodies.
What are the challenges or drawbacks of mRNA vaccines?
Fragility
As mentioned above, mRNA vaccine development has been historically stunted by engineering challenges. That’s because unprotected RNA is environmentally unstable, and RNases, enzymes that degrades RNA, are found in almost every type of prokaryotic and eukaroyotic cell. In fact, RNases are naturally secreted in human tears, saliva and mucus as a defense against microbial invasion. But now researchers have developed a delivery method that successfully protects RNA from enzymatic degradation, and enveloping mRNA with a lipid nanoparticle coating ensures the genetic messages reach their target cells unscathed.
Ultra-Cold Storage
The fragility of RNA also makes storage of this type of vaccine significantly more challenging. Basic laboratory protocol calls for unprotected RNA to be stored at -80°C to remain viable. Pfizer’s vaccine candidate requires similar subzero storage temps (-70°C). Unfortunately, many hospitals and treatment centers (especially in rural areas and developing countries) are unequipped and can’t afford to accommodate those requirements. In order to address these concerns, Pfizer has designed its own packaging, which uses dry ice to keep the vaccine cold enough to be stored for a few weeks without the need for specialized freezers.
Moderna, on the other hand, has announced that its vaccine candidate can remain viable for up to 6 months at -20°C and up to 30 days at normal refrigerator conditions (2-8°C). The difference likely has to do with the way the vaccine is encased. According to a recent NPR article, which quoted a Moderna spokesperson, the increased durability of the Moderna vaccine is its “lipid nanoparticle properties and structure.” Time will tell how each company manages manufacturing, distribution and storage demands.
What is needed for an emergency use authorization (EUA)?
The U.K. has already issued emergency approval of Pfizer's vaccine (Dec. 2, 2020), and Pfizer and Moderna have both filed requests for emergency use authorization (EUA) from the U.S. Food and Drug Administration (FDA). FDA review is a critical safeguard which helps ensure that vaccines are safe and effective for use. The FDA has scheduled meetings with the Vaccines and Related Biological Products Advisory Committee (VRBPAC) to thoroughly evaluate Pfizer's safety and efficacy data and review the EUA request on Dec. 10 and Moderna’s on Dec. 17.
It’s important to recognize that EUAs are not the same as FDA approval, but rather the tool that allows the unapproved use of medical products to diagnose, treat or prevent serious or life-threatening disease in times of emergency, and when no other alternatives are available. The FDA has provided guidance for the development and licensure of COVID-19 vaccines, which clearly requires “direct evidence of vaccine safety and efficacy in protecting humans from SARS-CoV-2 infection and/or clinical disease.”
What other candidates are showing promise?
There are many additional vaccine candidates in the pipeline, a number of which are showing promise. Two viral-vectored vaccines have also recently published press releases claiming preliminary success from their clinical trials. Both candidates use adenovirus shells, modified to infect human cells without causing disease, to deliver the genetic code for S protein, which results in host cell production of S protein and subsequent development of antibodies against the newly synthesized antigen. Viral-vectored vaccines are based on another type of next-generation platform that is less expensive to make and more stable than mRNA vaccines, often allowing them to be transported and stored at normal refrigerator temps.
On Nov. 22, 2020, AstraZeneca, a British-Swedish multinational pharmaceutical company, announced that its vaccine had an average efficacy of 70%. However, the company simultaneously revealed that there was dosing discrepancy between the testing sites of its trial (United Kingdom and Brazil). In the U.K., 2 different vaccine doses were compared, while the Brazilian site used only one. Unfortunately, this inconsistency caused a range in efficacy from 62%-90%, and further investigation is clearly needed.
On Nov. 23, it was announced that the second interim analysis of Sputnik V, the trade-name for a vaccine developed by the Russian company Gamaleya Research Institute of Epidemiology and Microbiology, showed a 91.4% efficacy 28 days after the first dose and 95% efficacy 21 days after the second dose of vaccine. At that time, 22,000 participants had received the first dose of vaccine and 19,000 had received the second of the 2-dose regimen.
Looking to the Future
Biology and Immunology
There are a number of questions surrounding front runner COVID-19 vaccine candidates that remain unanswered. Some of these have to do with the biology of the virus and/or host immune system, including how long the vaccine will remain protective. Will boosters be needed? And will these vaccines be safe and protective in pregnant women and children? Scientists are actively researching the immunopathology of SARS-CoV-2, and new information about the longevity of immunity is emerging regularly. But we still do not know how long the vaccine will remain protective. And the Phase 3 trials detailed above were conducted on non-pregnant participants, 18 years of age and older. Thorough investigation of the safety and efficacy of these vaccines in pediatric and pregnant populations is therefore still needed.
Logistics
Some questions have to do with the logistics of supply and demand. How will vaccine manufacturers and supply companies scale production to meet the needs of a pandemic world? When will the vaccine be available and how will it be distributed?
Logistical questions cannot be adequately answered until an EUA is in place. But the world is already planning for that day. On Dec. 1, 2020, the Advisory Committee on Immunization Practices (ACIP), a committee within the CDC that provides advice on how to use vaccines to prevent disease in the U.S., released some primary recommendations for COVID-19 vaccine distribution, suggesting that healthcare workers and residents of long-term care facilities should be offered the vaccine first. In the meantime, Pfizer has set up its own distribution campaign in preparation to meet the anticipated demand.
Vaccine Hesitancy
Another subset of questions has to do with public confidence and vaccine hesitancy. As case numbers continue to ebb and flow across the country, and many are experiencing local surges of SARS-CoV-2, weariness seems to be spreading as quickly as the virus itself. For some, the news of an effective way to prevent further spread of this disease could not come soon enough. For others, particularly those from underrepresented and underserved communities, it is a harbinger of a new kind of uncertainty and unease. Can we trust a vaccine that was developed so quickly? How do we address and prevent the recurrence of historical abuses and vaccine mishandling? Are there side effects that we should be concerned about?
In order to address these concerns, vaccine researchers and production companies must be open and transparent with their trial data, and scientists must address sources of vaccine hesitancy and misinformation directly. We must be honest about what we do not yet know and work to share the knowledge we do have in a way that empowers everyone to make informed decisions, which promote the health and well-being of ourselves and our communities.
