A year into the COVID-19 pandemic, with vaccine distribution ramping up across the US and other parts of the world, attendees of the Workshop on COVID-19 Vaccines: Efficacy & Safety received a hopeful message from keynote speaker Florian Krammer, Professor of Vaccinology at the Icahn School of Medicine at Mount Sinai:
“SARS-CoV-2 is not a hard virus to immunize against.”
Krammer’s message was echoed by a panel of experts in vaccine development and immunology, including Dr. Philip Dormitzer, who leads Pfizer’s viral vaccines research and development programs, and Dr. Randy Hyer, Senior Vice President of Global Medical Affairs at Moderna.
The workshop held on January 7, 2021 was organized by the CCICADA Center led by Rutgers University and the CEEZAD Center led by Kansas State University under support of the DHS Office of University Programs. The workshop discussed the COVID-19 vaccines under development, how well they work, what types of protection they provide, how they might contribute to a global strategy to combat the pandemic, and what questions remain unanswered. The two-hour event kicked off with Krammer’s keynote providing an overview on the COVID-19 vaccine development. This was followed by presentations by a panel of experts describing specific aspects of vaccine safety and efficacy. Joining Drs. Dormitzer and Hyer on the panel were: Fred Cassels of the PATH Center for Vaccine Innovation and Access, Adolfo García-Sastre of the Icahn School of Medicine Mount Sinai, Hana Golding of the FDA’s Center for Biologics Evaluation and Research, Karen Makar of the Bill & Melinda Gates Foundation, and Stanley Perlman of the University of Iowa.
IT’S ALL ABOUT VIRAL SPIKES
Coronaviruses are a family of viruses that affect humans and other animals. In humans, they usually cause relatively mild upper-respiratory, cold-like symptoms, and are thought to be zoonotic in origin. Recently, we have seen three coronaviruses make the jump from animals to humans causing severe respiratory diseases. These include the SARS outbreak in 2003, MERS in 2012, and now SARS-CoV-2 causing COVID-19.
SARS-CoV-2 consists of a lipid membrane with the viral spike, envelope and matrix proteins, and genomic RNA protected by the nucleocapsid protein on the inside; the viral spike protein on the surface of the virus forms the corona of the virus for which it is named (see Figure 1). The site on the virus that binds to the receptor on human cells is called the receptor binding domain (RBD), and it is part of the spike protein. When somebody gets infected with SARS-CoV-2, the body mounts an antibody response to viral proteins including the spike protein and the RBD, and these antibodies inhibit the binding of the virus to cells. There is growing evidence that the anti-RBD and anti-Spike antibodies correlate with protection from disease. In addition, the body also produces antiviral T-cells, which are a type of white blood cell that participates in immune response, and these T-cells also target viral proteins including the spike protein.
Vaccines produce an immune response by imitating key aspects of natural infection. For SARS-CoV-2, it’s all about the immune responses to the spike protein.
THE VACCINE DEVELOPMENT PIPELINE IS LARGE
The discovery phase of the vaccine for COVID-19 has moved incredibly fast. Panelist Karen Makar noted, “We have gone from a prototype pathogen to first in human in three months.”
The number of vaccine candidates is also extraordinary. The World Health Organization (WHO) lists 173 vaccine candidates in preclinical development and another 64 in clinical trials, seven of which are already licensed for use in some countries. These vaccine candidates are developed using a wide range of vaccine production technologies, or platforms. The spectrum of such platforms ranges from more traditional inactivated vaccines, to viral-vectored vaccines, to the newest mRNA vaccines produced by Pfizer and Moderna. In Krammer’s words, “This is the biggest experiment where we test different vaccine platforms, in humans, in parallel, against one pathogen.”
The scale of this experiment promises a wealth of new insights for scientists. Some of the platforms represented in late stages of the clinical pipeline of SARS-CoV-2 vaccine development include:
- Inactivated SARS-CoV-2. The Sinovac vaccine CoronaVac licensed in China uses inactivated SARS-CoV-2 virus.
- Viral-vectored vaccines that express the spike protein. The most developed of these vaccines are based on adenoviruses that have been engineered to express the spike protein but has been disabled from replicating within the vaccine recipient. Vaccines of this type include the Russian Gamelya vaccine and the CanSino vaccine which is licensed for use by the Chinese military. Vaccines developed by Janssen and AstraZeneca using this technology are in Phase III trials.
- Recombinant protein-based vaccines. Recombinant protein vaccines include those based on the spike protein and those based specifically on the receptor binding domain of the spike protein. Included in this category is the Novavax vaccine, which is in Phase III trials.
- Nucleic acid-based vaccines based on either DNA or RNA. Both the Pfizer and Moderna vaccines licensed for emergency use in the US are mRNA vaccines.
In describing the clinical pipeline, Krammer says, “There are so many candidates. It’s actually unbelievable.”
WHAT PROTECTIONS DO THE VACCINES PROVIDE?
COVID-19 can cause both upper and lower respiratory tract infections. Upper respiratory infections are associated with congestion and cold-like symptoms in the nose and trachea, while lower respiratory infections are associated with more severe symptoms such as lung inflammation and pneumonia.
In pre-clinical trials on non-human primates, all of the leading vaccine candidates induced an immune response that protected the lung from virus replication; however, none of them fully protected the upper respiratory tract system. Panelist Adolfo García-Sastre noted that protecting the lower respiratory tract is a priority for any vaccine in order to avoid the most severe cases of the disease and to reduce fatalities. But, to break the transmission cycle of an airborne respiratory disease like COVID-19, preventing virus replication in the upper respiratory tract is important but lacking so far.
Clinical trials indicate that many of the leading vaccine candidates induce strong neutralizing antibody responses in humans. Among the vaccines that may ultimately be fully licensed for use in the US, those developed by BioNTech/Pfizer and Moderna are farthest along and have demonstrated impressive results in Phase III trials.
The Pfizer trial included over 43,000 individuals among whom 170 cases of COVID-19 were reported—162 in the placebo group and 8 in the similarly sized group who received the vaccine, yielding an efficacy of roughly 95%. The trial included a subgroup of individuals aged 65-85, and the vaccine efficacy in this higher-risk group remained high at about 94%.
Moderna’s study included over 30,000 participants among whom 196 COVID-19 cases were recorded—185 in the placebo group and 11 in the group receiving the vaccine, yielding an efficacy of roughly 94%. Randy Hyer noted that Moderna worked hard to assure that the population in the Phase III trial was representative of the US as a whole, particularly with respect to communities that have been hard hit by the pandemic. They considered factors such as age, existence of comorbidities, and ethnicity, and observed good vaccine efficacy in all groups, though slightly lower with advanced age or comorbidities. Comparing vaccine efficacy in non-Hispanic whites versus efficacy in communities of color indicated very high vaccine efficacy in both groups.
The number of severe COVID-19 cases was much lower in the vaccine group for both the Pfizer and Moderna vaccines. In the Pfizer trial, only one of the ten observed severe COVID-19 cases was in someone receiving the vaccine. In the Moderna trial, none of the 30 severe cases were in people receiving the vaccine.
A graph of cases occurring over time in the Pfizer Phase III trial indicates that protection from disease is already beginning 10-12 days after receiving the first vaccine dose (Figure 3). Results of the Moderna vaccine Phase III trial look very similar.
Pfizer’s Philip Dormitzer was both surprised and pleased that efficacy is achieved so quickly after the first vaccination. He said, “Even at 21 days [after the first dose] there is very little neutralizing antibody detectable; yet, sometime between 10 and 12 days, you start to see efficacy, and it increases from there. Why do we have this early efficacy? Is it that the virus is very sensitive to neutralizing antibody and just a small amount is enough, or are there other mechanisms that are actually responsible for this early efficacy?” He also noted that trial participants receive a second dose at 21 days after the first, so data on duration of protection beyond 21 days following just one dose do not exist.
Vaccines can trigger a range of side effects that are collectedly referred to as reactogenicity. These side effects are often part of the body’s innate immune response to the vaccine or components within the vaccine formulation and can include injection site pain, headache, fatigue, muscle pain, elevated temperature, and mild flu-like symptoms. They may cause discomfort but are generally not life threatening . The side effects observed with the Pfizer and Moderna vaccines mostly fall into the category of reactogenicity. These effects are rather common with mRNA and viral-vectored vaccines, such as those based on the adenovirus, and they become more pronounced with the second dose. It may also be the case that people who have had COVID-19 have stronger reactions, even after the first dose. Reactions may also be stronger in younger populations.
There have been a very small number of people with more severe allergic reactions to the mRNA vaccines. Per Randy Hyer, reported rates for anaphylaxis after vaccination with these COVID-19 vaccines are now lower than 11/1,000,000 per a recent CDC ACIP presentation. These reactions happen within a few minutes of injection allowing for monitoring and treatment at the vaccination clinic should they occur.
As COVID-19 vaccines go into broad use, some rare side effects of vaccination will undoubtedly emerge. Stanley Perlman noted that Bell’s palsy—a sudden, usually transient, weakness in one side of the face—is being monitored as one potential rare side effect of COVID-19 vaccination. In Phase III trials of the Pfizer vaccine, there were 4 occurrences of Bell’s palsy in the vaccine group and none in the placebo group, while for the Moderna vaccine there were 3 occurrences in the vaccine group and one in the placebo group. This does not differ much from the background rate of Bell’s Palsy in the general population, but it is definitely something to monitor.
LICENSING IN THE US
In addition to the vaccines by Pfizer and Moderna that have already been approved for emergency use in the US, candidates from AstraZeneca (already licensed in the UK), Janssen, and Novavax are expected to release results of Phase III trials soon.
These clinical trials are part of the process—described by panelist Hana Golding—through which vaccines get approval from the FDA (Figure 4). During clinical trials, participants are added at each successive phase, going from tens of participants in Phase I to thousands in Phase III. During these trials, data on safety, immunogenicity, and efficacy are collected and evaluated. The end goal of the process is typically submission of a Biologics License Application (BLA) to the FDA for approval and licensure. This requires the company to provide information on manufacturing to assure consistency of manufacturing and quality of the product, as well as extended data on safety and efficacy over at least six to twelve months.
Golding emphasized that the Emergency Use Authorization (EUA) granted to Pfizer and Moderna is an unusual step put in place because of the urgency of the pandemic. EUA was granted based on review of Phase III interim data by the FDA reviewers and a panel of external experts (Advisory Committee) which gave the agency confidence in the efficacy and safety of the vaccines. Ultimately, the goal is for all vaccines used in the US to go through the full BLA licensure process.
Vaccination is underway in high income countries. Healthcare workers and other prioritized groups are presently being vaccinated, and vaccines will become more available to less prioritized groups throughout 2021.
Karen Makar of the Bill and Melinda Gates Foundation contrasted this with low and middle income countries where:
- Vaccines will not become widely available until late 2021 or 2022.
- Population coverage will be low.
- There will be poor coverage of healthcare workers, impacting the entire healthcare system.
- Community transmission will continue and will seed ongoing local and global outbreaks.
COVID-19 modeling from Northeastern University cited in the Gates Foundation’s 2020 Goalkeepers Report predicts that,
if the first 2 billion doses of vaccine go to high income countries instead of distributing them proportionally to the global population, nearly twice as many people could die from COVID-19 (Figure 5). The Gates Foundation views inequality in vaccine distribution as a looming global threat and is focused on getting vaccines to people in low and middle income countries.
The first big challenge is the number of vaccine doses needed. With seven billion people on this planet, we will need to manufacture billions of vaccine doses as quickly as possible; however, there is not currently the manufacturing capacity to do this. Makar said that we need to transfer technology and overcome regulatory hurdles to enable production in more countries. Fred Cassels described one instance where this is happening. A collaboration among Baylor College of Medicine, Dynavax, PATH, and the Indian pharmaceutical company Biological E Ltd has an RBD vaccine candidate currently in Phase I/II trials at five sites in India. This vaccine is moving toward Phase III trials that could lead to emergency use licensing, and once approved, Biological E has capacity to produce over a billion doses in a short period of time.
Pricing is another challenge. To be used in low and middle income countries, vaccines must be affordable.
Finally, low and middle income countries may require higher vaccination rates to control transmission. This will add to the number of vaccine doses needed and further strain manufacturing capacity and distribution capabilities.
A second wave of vaccine candidates, such as the one from the Indian company Biological E Ltd, is necessary to supplement those currently in use in order to surmount challenges in scaling and affordability. Quoting Makar, “It will take more than a couple of vaccines to get the job done.”
Adolfo García-Sastre noted that we currently have safe and efficacious vaccines against COVID-19 that are being distributed. But, this is not the end of the story.
Distribution must be accompanied by close monitoring for infections, disease, safety, and emerging new strains of the virus. Some of the questions asked by García-Sastre and other speakers include:
- Does SARS-CoV-2 change under vaccine immune pressure, potentially leading to vaccine failure or in some instances to vaccine-enhanced disease? So far, vaccine-associated enhancement of disease does not appear to be an issue. Scientists have been unable to induce vaccine-associated enhanced disease in animal testing, and there is no evidence that it is occurring in humans. Nonetheless, the fraction of people who have been vaccinated so far is extremely small—probably not enough to determine whether there is vaccine-associated enhancement of disease. As vaccines are used more, it will become more important to monitor for evidence of vaccine-associated enhanced disease.
- As the virus changes, will we need to update vaccines? The biggest concern would be viral changes to the receptor binding site targeted by the vaccines. The new UK variant, for instance, does not seem to affect vaccine-induced immunity significantly. In contrast, studies that have occurred since the workshop was held indicate that the South African variant seems to undermine, to a certain extent, vaccine-induced immunity. Global genomic surveillance will be important for monitoring key changes in the virus. Pharmaceutical companies like Pfizer and Moderna fully expect to monitor vaccine efficacy with respect to new variants, and if warranted, updates to the present vaccine formulations will be provided. It will also be important to follow the protocols established in clinical trials to assure efficacy and avoid opening potential avenues for “viral immune escape”, such as by lengthening the time between doses.
- How long does vaccine protection last?
- Why does SARS-CoV-2 spread so much more easily than SARS-CoV despite the use of the same cellular receptor?
- How much lower respiratory tract disease is present in patients presenting with mild COVID-19 symptoms?
- Which immune responses (antibodies, T-cells) are providing the correlate of protection?
- Why do we see high levels of protection after the first vaccination, before high levels of neutralizing antibodies are detected?
In closing comments García-Sastre reflected, “This virus is very easy to neutralize. We need to realize we have been extremely lucky in terms of vaccines with this pandemic. The next pandemic, we may not be so lucky.”