A number of the leading COVID-19 vaccines, including the first to market, rely on new platforms. These are technologies that have been developed over years, even decades, to target not just a single disease, but to take advantage of a key scientific development to affect a range of (current and future) clinical needs. Messenger RNA, which underpins the first two vaccine candidates is one such example – developed for other purposes and now deployed to combat a previously unknown virus.
At the Massachusetts General Hospital (MGH) Vaccine and Immunotherapy Center (VIC), we have been developing a self-assembling vaccine (SAV) platform that activates the immune system to attack specific targets. The core of the platform is a protein adapted from the bacterium that causes tuberculosis (called the protein core) and that powerfully displays fragments of proteins to the immune system. In our Self-Assembling Vaccine platform, any protein sequence from a new virus can be readily attached to the protein core to quickly make a vaccine. In 2014, for example, using Lassa virus, we went from viral sequence through pre-clinical testing in only 120 days. (Suffice it to say, that is fast!)
Knowledge of the immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or COVID-19) infection has been accumulating at an almost unimaginable pace. Dr. Patrick Reeves and his team at VIC, in collaboration with Voltron Therapeutics Inc., have developed a method for sifting through the knowledge and identifying the regions of the novel SARS-CoV-2 virus that the immune system targets most strongly. Each individual’s immune response is different, as indicated by the varying degree of illness that people experience once exposed to COVID-19. For this reason, rather than selecting a few precise sequences of the virus, Dr. Reeves and his colleagues chose an array of viral regions that appear again and again in different experiments. While a given individual may or may not respond well to a specific sequence within the region, most people’s immune systems will identify something within the pattern or grouping to which it will react in order to protect the person from the foreign invader – in this case, the coronavirus.
Will we need to vaccinate the whole world every year?
This next line of vaccines, like the SAV platform being developed by VIC, will prove to be very important. While the early reports and press releases from Pfizer, Moderna, and Astra-Zeneca are impressive and exciting, many unanswered questions remain. The first centers around durability of the immune response. More specifically, will we need to vaccinate the whole world every year? Unlike the front-running candidates, which are focused on stimulating antibodies in response to vaccine exposure, the SAV platform is aimed at training the T-cells (sometimes called memory cells) that are thought to provide longer lived immunity. T-cells are part of the adaptive immune system or active immune response; they recognize foreign substances, including infections, that they were exposed to in the past and then produce antibodies to attack the foreign body – kind-of like a precursor to or director of antibody production.
Regardless, second generation vaccines, like the one being developed at VIC, are critical for the overarching response
Next, there is the question of access and distribution of vaccines that require ultra-low temperature storage and multiple doses. Plus, safety concerns may emerge as follow up continues with ongoing trials. While rare and hopefully not serious, untoward side effects or adverse reactions could limit the number of people who should otherwise receive the vaccine. Progress thus far has happened at record speed; therefore, we dare to hope that the frontrunners will be enough to suppress or eliminate COVID-19 worldwide. Regardless, second generation vaccines, like the one being developed at VIC, are critical for the overarching response. In addition, the SAV platform can be applied to emerging infectious and other diseases where the immune system needs to be targeted, including coronaviruses in general, viral and bacterial infections, the next pandemic, and even cancer.
Written By Mark Poznansky, MD, PhD, FCRP, FIDSA
Edited By Jacki Hart, MD
Vaccine development for COVID-19 is a fast-moving topic. Private industry, academics, and government agencies are working together at rapid speed to generate viable options for billions of people throughout the world without sacrificing safety or introducing unforeseen risk. The goal, as with any vaccine, is to stimulate your immune system to make antibodies against the SARS-COV-2 virus, thereby protecting you from getting sick with coronavirus. The urgency to control the spread has translated into testing of well-known, theoretical, and brand-new technologies. Brilliant minds are hard at work, around the clock, to not only design and test vaccines, but to also determine systems for distribution and administration to help abate the global crisis.
There are hundreds of vaccines in the pipeline in various stages of investigation, including 54 (as of this writing) that have advanced to the stage of being tested on people and 10 in late stage (known as Phase III) clinical testing. As of November 2020, there are two that stand out as close to acceptable levels of effectiveness and safety; therefore, plans for mass production, distribution and administration are also underway.
Pfizer and Moderna Both use mRNA Technology
The news that has grabbed recent worldwide attention include announcements by Moderna and Pfizer/BioNTech that Phase III clinical trials of their mRNA vaccine candidates show nearly 95% effectiveness. Many drained global citizens are starting to imagine solutions for this pandemic. Dr. Anthony Fauci, Director of the United States (U.S.) National Institute of Allergy and Infectious Diseases (NIAID) went so far as to claim that “it’s not going to be a pandemic for a lot longer because I believe the vaccines are going to turn that around.”
There are many caveats and precautions to keep in mind, however, not only with vaccine development and confirmation of efficacy and safety, but also with distribution and administration of the shots.
Vaccine Safety & Effectiveness
While these encouraging results bring us closer to a solution, it’s important to understand what they mean. In clinical trials, such as those conducted by scientists at Pfizer and Moderna, there are two groups of people, neither of whom have been previously infected with COVID-19. Participants are randomly assigned to receive injection of either placebo (consisting of saline water) or the experimental vaccine candidate. The participants, doctors, and healthcare providers administering the injection do not know who received vaccine and who received placebo; this is called a randomized, controlled, blinded clinical trial. In medicine, we refer to that design as the “gold standard” of research because we can rely on the results being scientifically valid, rather than the positive effects being from nothing more than luck or chance. Those who received the experimental vaccine in both the Pfizer and the Moderna studies were 90 to 95% less likely to develop coronavirus than those who received placebo injections. For example, in the Pfizer investigation, 170 people, out of almost 44,000 recipients have contracted the virus to date; 162 of them had received placebo, while only 8 had received the vaccine.
This is promising and exciting. After many months of being sequestered and feeling secluded, we have legitimate reason to feel hope.
After many months of being sequestered and feeling secluded, we have legitimate reason to feel hope.
Now, Pfizer/BioNTech submitted an application for Emergency Use Authorization (EUA) to the U.S. Food and Drug Administration (FDA). The company will continue ongoing research to assess long term immunity (meaning – for how long the vaccine can protect you from contracting the virus), potential negative effects that might occur over time, and ability to confer immunity following exposure to the virus. The last question will explore whether the vaccine is protective if you receive it after you’ve been around someone who has COVID-19. One important element already determined is that it takes roughly 28 days following the second dose of the Pfizer mRNA vaccine until antibodies develop – a crucial step toward conferring immunity.
Vaccine Distribution & Administration
As rates of infection in parts of America and Europe approach their highest levels, everyone eagerly awaits the release of this vaccine. Once authorized by the FDA, public distribution will be complicated and will limit return to our pre-pandemic lives, as will outstanding questions about safety and effectiveness.
Widespread vaccination in America is still many months away. We must remain vigilant, continue to do everything in our individual and collective power to slow the spread of the virus. Wearing masks, physically distancing, avoiding social gatherings, and practicing hygiene remain the mainstay for stopping the spread of COVID-19 and saving lives. This will be the case for a significant period of time, even after a vaccine is available. Dr. Fauci estimates that high-risk Americans and healthcare workers will be among the first recipients of the vaccine. Ambitious estimates suggest that a sizeable proportion of the U.S. population will receive the vaccine by mid to late spring. But, Dr. Fauci warns, such a “guesstimate” assumes that everything proceeds without setbacks, mistakes, or unanticipated risks.
But, Dr. Fauci warns, such a “guesstimate” assumes that everything proceeds without setbacks, mistakes, or unanticipated risks
Concerns have also been raised about how Pfizer will manufacture and ship the vaccine to hospitals and pharmacies across the globe. Pfizer is manufacturing the vaccine in Kalamazoo Michigan and in Belgium; for Americans, the majority of vaccine doses will come from the Great Lakes state. It is up to federal and state governments, however, to decide to whom to appropriate the doses and the number to request. As mentioned, the vaccine preparation uses mRNA that, once inside your body, enters cells and is coded to produce a protein that mimics spikes on the outside of the coronavirus. These spike proteins “trick” your immune system into responding to this foreign entity as if it were coronavirus.
The mRNA needs to be kept at temperatures well below zero (more specifically, negative 70 degrees Celsius, which is equivalent to negative 94 degrees Fahrenheit); otherwise, the vaccine will denature (fall apart) and be rendered ineffective and unusable. Pfizer has designed reusable boxes filled with dry ice to keep the vials of vaccine cold enough, and shipping companies, including UPS and FedEx, have designed special compartments to send and deliver the vaccine vials. These special containers hold between 1000 and 5000 vials.
One potential advantage of the Moderna candidate, which relies on similar mRNA and, therefore, still requires cold storage, is that the temperatures needed for this vaccine to stay stable up to 30 days resemble standard refrigerators and freezers available in pharmacies and hospitals.
Many details are yet to be determined, including that Pfizer reports the plan to ship 50 million doses in December. Twenty-five million of those vials are slated for distribution in the U.S., while the other 25 million will go to other countries. That means that 12.5 million Americans can be vaccinated during this first round, since each person receives two doses, three weeks apart.
12.5 million Americans can be vaccinated during this first round, since each person receives two doses, three weeks apart.
Meanwhile, the Bill & Melinda Gates Foundation is at the forefront of global distribution, working with international partners to both quickly develop the second generation of vaccines more suitable for low and moderate income countries and prepare systems for distribution. GAVI, Vaccine Alliance and Coalition for Epidemic Preparedness Innovations (CEPI) are co-leading the efforts of the Access to COVID-19 Tools (ACT) Accelerator to ensure equitable access to COVID-19 tests, treatments, and vaccines. As Melinda Gates says “COVID-19 anywhere is COVID-19 everywhere.”
As Melinda Gates says “COVID-19 anywhere is COVID-19 everywhere.
Distribution Within States’ Purview; But Dollars Fall Short
In the U.S., the logistics of vaccinating and tracking millions of citizens will be left largely to state governments. The Centers for Disease Control and Prevention (CDC) in the U.S. has committed to providing 340 million dollars to the states for these distribution efforts; however, local health departments anticipate much higher costs and have requested another 8.4 billion dollars from the U.S. Congress to adequately and appropriately fulfill this duty. Comprehensive online systems are necessary to keep track of who has received vaccinations. Insufficient funding will slow down the rate of vaccination, especially among citizens who are hard to reach, as well as the process of following who has received their first and second doses. States with large rural populations pose particular challenges for the administration of the vaccine due to the cold storage requirements.
States with large rural populations pose particular challenges for the administration of the vaccine due to the cold storage requirements.
Each of Us Has a Role in Curbing COVID-19
Another problem involves potential resistance to taking the vaccine. There is a worldwide movement of anti-vaxxers, which is based on false data and amplified by social media. Plus, others feel some degree of skepticism because of the speed with which the vaccines are being developed.
But, as Kavita Patel, MD, a prominent physician and public health expert, points out “vaccines don’t save lives; vaccinations do.”
Kavita Patel, MD, a prominent physician and public health expert, points out “vaccines don’t save lives; vaccinations do.”
Lessons from the Past
When Elvis Presley was vaccinated on national television in 1956, the polio immunization rate among teens skyrocketed and incidents of polio went down by 90% in just four years. History shows that when prominent Americans, especially from marginalized or high-risk communities, use their platforms to lead by example, people pay attention and heed their advice. Nowadays, those messages can reach far and wide through social media influencers, when first vetted by public health experts.
Many questions remain unanswered and unexpected challenges will arise along the way. The aim is for scientists and authorities to work hand-in-hand to mitigate polarization and to not only produce safe, effective vaccines but also readily distribute and administer them as swiftly, efficiently, and equitably as possible.
In the meantime, our job as citizens remains to limit the spread of COVID-19 even after the vaccine is available and distribution has begun. This virus will circulate in the population for a long time to come. Like a mantra, we say again and again: wear masks, physically distance, avoid social gatherings, and practice hygiene. Plus, while availability of testing has improved, progress is still needed for widespread application in the U.S. and receipt of rapid results. As we face the last quarter of the year since COVID-19 was identified, we still need to set testing as a top priority by enhancing supplies and, perhaps, the possibility of self-administered home testing.
Written By Rohan Prabhu & Jacki Hart, MD