Mass. Eye and Ear and within it, the Grousbeck Gene Therapy Center, is an academic research center devoted to developing therapeutic gene transfer methodologies in modern medicine. To date, much of the research in the center has focused on genetic diseases, including several forms of blindness.  

However, our leading Adeno-associated viral (AAV) vector platform at the lab of Prof Luk H. Vandenberghe (Director of Grousbeck Gene Therapy Center) is not limited by type of disease. AAV vector is a delivery vehicle, made from a harmless adeno-associated virus, to transport any gene of interest to a cell or host organism. Vandenberghe lab has now leveraged this expertise to create first gene-transfer vaccine candidate (AAVCOVID19) against coronavirus.  

I manage the centralized facility that specializes in production of AAV viral vectors as the Associate Director of Gene Transfer Vector Core (GTVC). We generate viral vectors for investigators at the Harvard University and outside community to accelerate their basic, translational, preclinical research programs. I have a team of 4-5 scientists who work on designing payload of vector, engineering genes of interest, producing high quality and amounts of vectors. We are also supporting AAVCOVID19 vaccine development efforts by generating the critical material used in animal studies for this program. Besides, I am also helping the vaccine program in other managerial activities working with the AAVCOVID19 research team.

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 is a gene-based vaccine - which means - the active component of the vaccine is a gene that encodes for SARS-CoV-2 Spike antigen. 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 disease from becoming severe. AAVCOVID experimental vaccine is planned to be administered via intramuscular route with a single administration (‘prime-only’) at a low dose.

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 desirable in the context of an emerging pathogen or pandemic. 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.

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. 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. 

Scientifically, the particular AAV technology in the AAVCOVID vaccine leverages simple yet compelling biological features for its use as a vaccine including: 

* the absence of pre-existing immunity against this AAV technology in human populations that could otherwise reduce the effects of vaccine.

* a demonstrated mild pro-inflammatory profile compared to most other AAVs which makes them less desirable for vaccine use. 

* The ability to induce antibodies quickly after injection, which is relevant given the urgency of the current crisis.

These and many other advantages over existing technologies makes it a very attractive modality as vaccine. 

In addition, as any biomedical breakthrough for complex diseases doesn’t occur in isolation anymore – it needs mentioning that our collaborations with academic, industries, manufacturing, and innovation management partners came about in a never-seen before speed and engagement. A consortium of industry experts and academic collaborators with deep experience in vaccine development, regulatory affairs, AAV manufacturing helps bring together the needed expertise to get to clinic in the fastest timeline possible. It is truly a scale and timeline matching the unprecedent urgency of novel pandemic in front of us.  

Adeno-associated virus or AAV used in AAVCOVID19 vaccine is a very different technology platform than Adenovirus vaccine being developed at the Oxford. 

AAV is a small vector system, not known to cause any human disease, and 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 for diseases of the eye and neuromuscular system in various territories including the US. From those studies we know that its extensive human use as a gene transfer vector has overall been well tolerated. To address the safety of AAVCOVID as vaccine candidate in specific are underway and planned. 

Adenoviruses, on the other hand, are much larger viruses. 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. 

From a vaccine perspective, they also are very distinct in the type of immunity they elicit. Adenoviral vaccines are known to lead potent cellular immunity, whereas AAV can elicit more potent antibody-mediated or humoral immunity.

There are, however, also analogies to adeno and AAV approaches. Generally, both are gene-based vaccine using a replication incompetent (or replication defective) viral vector system. In addition, both used SARS-CoV-2 Spike protein as an antigen (however different programs may use slightly different Spike designs). Both have been used and explored in gene therapy as well as gene-based vaccine studies. 

Moderna is mRNA-based vaccine and does not utilize viral vectors for delivery making it a diverse class of vaccine to considering its unique challenges and outcomes. 

AAVCOVID uses the technology platform that is currently not explored by others yet, and has a number of highly compelling features. These distinct features and emerging biology have persuaded the members of the AAVCOVID consortium to devote themselves to bringing this vaccine 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 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.

No that would not be an issue. Due to the novelty and scale of the SARS-CoV-2 pandemic, there also is 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. Scientists and public policy makers largely agree that population immunity is needed to stem the epidemic. 

Costs for AAV vaccine will be affordable.  Need of small doses to elicit immunity, and efficient delivery will make product available for larger population. This contrasts with AAV technology being used in Gene therapy field where larger doses are used, or other vaccine efforts for covid-19 that are not using advantage of vector delivery system. 

Per FDA guidelines, any experimental vaccine requires clinical testing in various phases to establish safety and efficacy before regulatory agencies will consider approval for its 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.

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 later 2020. The first trials would be through the MGH Translational Research Center, and they may include front-line health care workers as some participants. We will continue to update information on trial enrollment on this website and will post the trial on clinicaltrials.gov at the appropriate time. 

As a researcher, I feel ever-enhanced sense of responsibility to help and support efforts in AAVCOVID vaccine program. In my career as a biomedical scientist for 20 years, I have been working on specific aspect of a bigger question of a certain disease (like Cancer or Alzheimer’s disease) and the impact of my work was not immediately connected to patient. 

But now, my every day work is being implemented and helping in solving a crisis at hand that has affected our lives as we know, health, and economy at large. The problem is urgent, but with a promising solution in our hand, we are only limited by number of hours in a day to work and progress.

The message at this point is that we will live with this virus or its strains for coming months, and practices - like washing hands with soap, keeping physical distance, and wearing masks when you are in proximity to other individuals - are still the best protection against infection. 

A long-term solution is - vaccination approaches for which we are all working hard. Earlier, scientists have found solutions against plague, smallpox, and polio and likewise we will get rid of Covid19 too.

In addition, if you would like to contribute to the accelerated development of this vaccine with the goal of conducting human clinical testing and making it available to patients as soon as possible. Please reach out to Mass. Eye and Ear COVID-19 Vaccine Development Fund.