COVID-19 Vaccine: Frequently Asked Questions
The AAVCOVID vaccine program seeks to develop, manufacture, and test an experimental pre-exposure prophylactic gene-based vaccine for SARS-CoV-2 and the prevention of COVID-19.
AAVCOVID aims to elicit an anamnestic response to SARS-CoV-2 that targets its Spike (S) protein on the viral envelope in order to ultimately achieve protection from infection and/or COVID19 disease. An anamnestic response is the rapid production of antibodies after stimulation by an antigen, which is the Spike (S) protein in this case. If a vaccine is successful, those antibodies then protect the vaccinated individual.
AAVCOVID experimental vaccines are planned to be administered via intramuscular route with a single administration (‘prime-only’) at a low dose.
AAVCOVID is a gene-based vaccine in which the active component of the vaccine is a gene that encodes for SARS-CoV-2 Spike antigen. Unique about the AAVCOVID program in comparison to other gene-based COVID19 vaccine programs is the use of the AAV gene transfer platform to express and induce immunity toward the SARS-CoV-2 Spike antigen.
The AAVCOVID Vaccine Program is a novel, gene-based vaccine strategy which seeks to deliver inside the muscle, genetic fragments of the coronavirus that causes COVID-19, in order to build an immune response. The immunity that the body builds over time can, if successful, protect the host from viral infection and/or COVID-19 symptoms or disease.
There are many different classes of technologies that have successfully been used in the past for vaccination or immunization. Other technologies are more novel and are being explored as they may have certain advantages. Gene-based vaccines are a newer class of vaccines that can be developed more rapidly than some of the more traditional vaccine modalities, a property particularly relevant in the context of an emerging pathogen or pandemic.
A gene-based vaccine introduces into the host a piece of modified genetic material from the SARS-CoV-2 coronavirus. That genetic material carries a program that cells close to the site of injection read and use to generate a protein of the coronavirus called an antigen. Traditional vaccine approaches work to induce immunity as well; however, they do so by directly administering the antigen, not the genetic information for the antigen, to the subject.
It is the antigen that ultimately induces immunity in the host. The speed, the quality, and the level of immune response may then lead to protective immunity that prevents the virus from getting a foothold upon exposure and/or prevents any disease from becoming severe. To carry that genetic information into the cells, several gene transfer technologies are available, and many of those are currently being explored for COVID-19 vaccines including DNA, mRNA, Adenovirus-based, MVA-based, and other gene-based strategies.
A key differentiating feature of AAVCOVID is that it uses AAV to enable gene transfer. AAV is a class of technologies that has been used clinically for almost 25 years in thousands of patients. It is incorporated in three drugs which have been approved by regulatory agencies in various countries across the world, two of which have been approved by the US Food and Drug Administration.
AAVCOVID is unique amongst the active COVID-19 programs as it leverages the safety and potency of AAV technology. AAV is a vector, or delivery vehicle, made from a harmless virus called the adeno-associated virus.
As a virus, AAV is not known to cause disease in humans. Moreover, molecular modifications to AAV have been done over the past 40 years to delete key elements to effectively further neuter it as they cannot replicate independently and thus make them even safer. The end result of this neutering is referred to as a replication-defective virus, recombinant vector, or viral vector. This gene transfer platform has been used to deliver gene therapy medications to certain areas of the body, including in Food and Drug Administration (FDA)-approved medications for diseases of the eye and neuromuscular system.
No, and yes.
No, because AAV is a very different technology platform that Adeno (notwithstanding the possible name confusion with adeno-associated virus or AAV). AAV is a vector system derived from a small parvovirus that is not associated with any human disease. AAV carries a single stranded DNA genome of about 5,000 base pairs in length. AAV technology is currently actively being explored as a gene transfer technology in clinical trials in several diseases other than COVID-19 and has several approved products on the market in various territories including the US.
Adenoviruses, on the other hand, are much larger viruses with a much longer double stranded DNA genome. Most adenoviruses are associated with diseases in humans (and animals) that range from the mild and transient symptoms such as in a common cold to, much more rarely more severe disease.
AAV as a virus is not known to lead to human disease and in its extensive human use as a gene transfer vector it has overall been well tolerated. Studies to specifically address the safety of AAVCOVID are underway and planned.
From a vaccine perspective, with what is known from prior studies with adenoviral and AAV-based vectors, they also are very distinct in the type of immunity they elicit. Adenoviral vaccines are known to lead to potent cellular immunity, whereas AAV can elicit more potent antibody-mediated or humoral immunity.
Adenoviral vaccines have been explored as a vaccine much more than AAV. AAV has only been tested once as an experimental prophylactic vaccine for HIV (NCT00482027).
There are, however, also analogies to these two otherwise distinct approaches.
Generally, both approaches are gene-based vaccine approaches (see above). In addition, both use the SARS-CoV-2 Spike protein as an antigen (however different programs may use slightly different Spike designs). Adeno and AAV are both replication incompetent (or replication defective) viral vector technologies. Both have been used and explored in gene therapy as well as gene-based vaccine studies.
The potential for name confusion stems from the fact that AAV or adeno-associated virus originally was discovered as a laboratory contaminant of an adenoviral preparation. In fact, it is believed that adeno (or other viruses) are needed to help AAV replicate and propagate, making AAV an helper-dependent or dependovirus. Adeno and AAV are however highly distinct viruses from divergent viral families with vastly different properties as a vaccine and otherwise.
Scientists and public policy makers largely agree that population immunity is needed to stem the epidemic. Due to the novelty and scale of the SARS-CoV-2 pandemic, there also is general consensus that for the global community to have a vaccine as quickly as possible, multiple parallel efforts need to be undertaken, leveraging many, if not all, valid vaccine technologies.
AAVCOVID is an approach toward a vaccine for COVID-19 that builds on a technology platform that is currently not explored by others, yet has a number of highly compelling features. These distinct features have persuaded the members in the AAVCOVID consortium to devote themselves to bringing this vaccine option forward to clinical studies.
The distinct features of the AAVCOVID vaccine program are:
- AAV technologies have generally been very safe in hundreds of clinical studies in thousands of subjects with multiple AAV technologies over the past two decades. This platform has led to the approval of three gene therapy products in various parts of the world, including two by the US FDA. Moreover, often the doses used in these clinical studies have been far higher than what an AAVCOVID dose is anticipated to be. In general, adverse safety findings with AAV have only been noted at very high doses. The particular safety profile of AAVCOVID will need full assessment to confirm whether the findings of the AAV platform extend to AAVCOVID.
- AAV can induce rapid and high levels of antibodies to an antigen following a single intramuscular injection in laboratory studies. These antibody levels have been found protective in infection models of other respiratory diseases (e.g., Flu). While the immunity from AAV is largely antibody-driven, the AAVCOVID technology also has a component of cellular immunity that may contribute to achieving protection. Under the assumption that to achieve SARS-CoV-2 protection, high level neutralizing antibodies are the first and main line of defense, AAV is believed to have these properties from a single administration (i.e. prime only, rather than a prime-boost regimen). A prime only vaccine would avoid the need for multiple visits to a healthcare provider and enable a person to achieve immunity from a single injection.
- AAV benefits from an extensive and established capacity and industry to manufacture at scale. This capacity is present now at various sites across the globe to produce AAV-based medicines. This capacity could deliver a large number of doses of an AAVCOVID vaccine in the eventuality that AAVCOVID is safe and efficacious in clinical studies. Also, further scaling to reach even larger populations may be feasible as methods are relatively transferable to existing capacity that is used for other biologic manufacturing processes.
- Among the gene-based vaccine modalities, AAV performs gene transfer highly efficiently, thus reducing dose and increasing the scalability of AAVCOVID compared to other gene-based modalities.
- The particular AAV technology that AAVCOVID leverages has unique biological features attractive to its use as a vaccine including:
- the absence of inhibitor (or pre-existing immunity) levels in human populations that could otherwise reduce the immunizing effect of AAVCOVID.
- a demonstrated mild pro-inflammatory property of the AAVCOVID technology that differentiates it from most other AAVs that are less inflammatory, thus less desirable for vaccine use.
- The ability to induce antibodies quickly after injection, which is relevant given the urgency of the current crisis.
Population (or herd) immunity is achieved when a virus is unable to find new hosts to infect as most are immune to the infection. It not only can limit the spread of the virus, population immunity can possibly and eventually exterminate the coronavirus entirely. Achieving population immunity will reduce or eliminate new infections from occurring, but also the number of individuals with symptoms, disease, and the number of fatalities due to COVID-19.
For society to go back to a version of normal, the risk to and fear of individuals to be infected in public places, become ill, or to spread it to your family and neighbors needs to be greatly reduced, if not eliminated. Only when the current measures such as social distancing, work-from-home, and shut-downs can be halted without significant risk to the health of individuals, the economy can fully rebound and work, personal, and social life can return to a sense of normalcy.
To achieve population immunity with the least amount of human suffering a vaccine will be needed. To varying degrees of success, vaccines to other pathogens have proven this point repeatedly as one of the most powerful medicines and medical approaches ever invented. This is why in this current crisis, multiple vaccine efforts need to be progressed in parallel to increase the chances that one or more will be available in the shortest amount of time.
Work began on the vaccine in January 2020 shortly after the first genetic sequences from the epidemic outbreak of coronavirus in Wuhan, China became available in the laboratory of principal investigator Luk H. Vandenberghe, PhD, Director of the Grousbeck Gene Therapy Center at Massachusetts Eye and Ear and Associate Professor of Ophthalmology at Harvard Medical School.
Dr. Vandenberghe and his research team initiated work based on observations that he had made over a decade ago in HIV and Flu that illustrated the unique utility of a particular AAV technology as a vaccine. Over the subsequent weeks when the epidemic reached pandemic proportions, Dr. Vandenberghe accelerated the development and teamed up with Mason Freeman, MD, Director of the Translational Medicine Group of the MGH Center for Computational and Integrative Biology and the MGH Clinical Research Program.
Dr. Mason is spearheading efforts to develop clinical studies intended to establish safety and efficacy of the experimental vaccine as Mass General Hospital. Together, they brought in a group of experts and capabilities in an unprecedented community effort that crosses institutional boundaries, and this academic-industry consortium is leading AAVCOVID to clinical studies.
If the AAVCOVID vaccine program continues to advance through each phase of safety and efficacy testing and manufacturing process check points, clinical trials may begin in early 2021. The first trials will likely begin overseas in areas where COVID-19 vaccines are not yet widely available, with a goal towards global distrubition in developing countries.
Per FDA guidelines, any experimental vaccine requires clinical testing in various phases to establish safety and efficacy before regulatory agencies will consider approval for use in the general public. In addition, many vaccine doses will have to be produced to enable broad availability which requires large scale manufacturing over time. Normally, the process of approval and production takes years, however the AAVCOVID programs is pursuing various strategies to accelerate these developments while maintaining the integrity of the process to ensure the safety of subjects.
As for any novel vaccine, careful studies, including clinical trials, are needed to determine vaccine safety. Given the broad use of many vaccines, safety is paramount. Various safety studies on AAVCOVID are therefore underway and being planned.
Several safety considerations make AAV compelling a vaccine technology. The AAV platform has been used in clinical studies for over 20 years in thousands of patients, primarily in gene therapy studies for inherited disease, generally without major safety issues. Moreover, these studies typically use doses that are much higher than what is anticipated to be used for AAVCOVID. In fact, AAV technology has been incorporated into three drug products that have been approved by regulatory agencies in various countries across the world, two of which have been approved by the US Food and Drug Administration.
While certain versions of AAV technology have been proven to be safe in several clinical studies and approved drugs, there are specific elements of AAVCOVID that are novel and have not been tested for safety. These include the specific AAV vaccine vector and the expression of SARS-CoV-2 spike antigen.
The goal of this gene-based vaccine is to obtain complete and durable prevention against the virus that causes COVID-19 in healthy populations. A vaccine may be able to help build herd or population immunity in the future, meaning a population has enough people vaccinated against the disease to make future spread unlikely.
The way a healthcare provider would give AAVCOVID is very similar to the flu shot namely via an injection into the muscle. Vaccines are expected to be safe in large population, and the same standards will be applied to AAVCOVID. The exact specification of any possible side-effects will be determined over the course of the clinical studies.
There are many key experts and partners collaborating on the AAVCOVID19 vaccine project.
This multi-institutional program is led by principal investigator Luk H. Vandenberghe, PhD, Director of the Grousbeck Gene Therapy Center at Massachusetts Eye and Ear, and a world-renowned leader and pioneer of viral gene transfer and therapeutic gene transfer. Dr. Vandenberghe is working in conjunction with Mason Freeman, MD, Professor of Medicine at Harvard Medical School and Director of the Translational Medicine Group of the MGH Center for Computational and Integrative Biology and the MGH’s Translational Research Center, a clinical research center within the MGH Research Institute.
In addition to working with Mass. Eye and Ear and Mass General Hospital, the team is collaborating with scientists throughout Mass General Brigham, Harvard Medical School, and academic collaborators across institutions nationally and internationally. The broader AAVCOVID consortium also includes experts from the biotechnology and pharmaceutical industry with deep experience in vaccine development, regulatory affairs, AAV manufacturing, and development of biologics. The consortium of industry experts and academic collaborators helps bring together the needed expertise and capabilities to get to clinic in the fastest timeline possible. Through a significant effort, Mass General Brigham Innovation manages the commercial interactions and intellectual property to expedite progression of AAVCOVID to the clinic.
The AAVCOVID vaccine project is currently supported by philanthropic donations, and fundraising to further support and accelerate the program is ongoing.
The initial support came from individuals on the Mass. Eye and Ear Board of Directors. The research is funded by philanthropic support led by Wyc Grousbeck, Boston Celtics lead owner and CEO and Mass. Eye and Ear Chairman, his wife Emilia Fazzalari, CEO of Cinco Spirits Group LLC, the Grousbeck family, and others.
Fundraising for additional milestones along the AAVCOVID development will explore additional philanthropy, grants, support from foundation, and commercial partners.
Dr. Luk H. Vandenberghe is the Principal Investigator on the AAVCOVID effort and leads the scientific and preclinical efforts in the program. He is a leader in the field of gene transfer for therapeutic and vaccine applications. His research led to the development of some of the leading technologies currently in clinical studies and gene therapy product, such as AAV9. His work in his home department of Ophthalmology at Mass. Eye and Ear and Harvard Medical School is focused on genetic forms of blindness. He is an author on more than 80 publications and an inventor on more than a dozen technologies, several of which are in clinical studies and one of which is incorporated into a currently licensed gene therapy drug for Spinal Muscular Atrophy Type 1. He trained at the University of Leuven, Belgium and University of Pennsylvania before joining Harvard Medical School. He is the co-founder of several gene therapy biotech companies, serves on the Board of 2 science-related non-profits. Importantly, AAVCOVID is being development entirely out of Mass. Eye and Ear and Mass General Brigham with no involvement of any of Dr. Vandenberghe for-profit interests.
Dr. Mason Freeman, MD is the clinical lead on the AAVCOVID program. Dr. Freeman is a professor of medicine at Harvard Medical School, Chief of the Lipid Metabolism Unit at Massachusetts General Hospital (MGH), and Director of the Translational Medicine Group of the MGH Center for Computational and Integrative Biology and the MGH Clinical Research Program. The Freeman laboratory explores lipid trafficking in and out of macrophages, and has been continually funded by the National Institutes of Health since 1990. Dr. Freeman also oversees a clinical development team, which created a novel oral anti-diabetic drug that is now entering phase 3 clinical trials. Earlier, Dr. Freeman directed the Novartis Translational Medicine Program for Cardiovascular & Metabolic Diseases and served as the company’s Global Head of Biomarker Development. Dr. Freeman has provided consulting services to numerous life science startup companies, either independently or through his work at 5AM Ventures, an early-stage life science venture firm that has helped create more than 20 companies. In addition, Dr. Freeman serves on the board of Envoy Therapeutics, a neuroscience company acquired by Takeda in 2012, and holds a key medical advisor role at Relypsa, which developed the first chronic oral therapy for hyperkalemia.
Roger Kitterman is a member of the strategic advisory team and leads the partnering efforts for the AAVCOVID project. Mr. Kitterman is Vice President, Venture and Managing Partner of the Mass General Brigham Innovation Fund. He also serves as Executive Director of the Boston Biomedical Innovation Center, an NHLBI funded program to develop technologies in the areas of heart, lung, blood, and sleep. Mr. Kitterman is an experienced venture capital investor with more than 20 years in the industry and has guided multiple venture-backed companies through the earliest stages of development. He has also been the startup CEO for three venture-backed companies, is a founder of Mass Medical Angels, and has served as a partner at life science-focused venture funds in the Boston area. He has backed a wide range of life science companies, including Adheron Therapeutics, CoStim Pharmaceuticals, Daktari Diagnostics, Provasculon, and RaNA Therapeutics.
Katrine Bosley is a member of the strategic advisory team and is a member of the Board of Directors of Mass. Eye and Ear. Ms. Bosley is a biotechnology entrepreneur and also currently serves as Chairman of the Board of Arrakis Therapeutics and as a Board member of Galapagos NV,, and of Genocea Biosciences. She was CEO of Editas Medicine and was also CEO of Avila Therapeutics. Earlier roles included positions at Adnexus Therapeutics, The Broad Institute, and Biogen, and Ms. Bosley also served as the Chair of the Emerging Companies Section of BIO.
A large group of individuals within the Grousbeck Gene Therapy Center, Mass. Eye and Ear, Mass General Hospital, Mass General Brigham, Harvard Medical School and at other academic institutions are key collaborator on AAVCOVID. In addition, a group of external advisors, each with deep experience in the biotech and pharmaceutical industry are actively contributing to the success of AAVCOVID. To date, over 50 scientists, engineers, regulatory experts, contracting agents, and people from many other disciplines are involved in the effort.
The spread of COVID-19 has reached pandemic proportions, putting the global community at risk and threatening to overwhelm healthcare systems. The establishment of immunity through vaccination is likely the most effective strategy to stem this pandemic while minimizing further major loss of life and enabling a return to economic and social normalcy.
Mass. Eye and Ear and within it, the Grousbeck Gene Therapy Center, is pioneering the development of gene transfer approaches to intervene across areas of medicine. To date, much of that research has focused on genetic diseases, including a number of forms of blindness. However, the AAV technology platform is not limited by type of disease. Dr. Vandenberghe and his team were able to leverage their expertise in gene transfer and AAV and apply it to the creation of the first gene-transfer vaccine using AAV technology.
Mass. Eye and Ear seeks funding to significantly accelerate development of this vaccine with the goal of conducting human clinical testing and making it available to patients as soon as possible. For more information, visit the COVID-19 Vaccine Development Fund.