Vaccine Boot Camp at Warp Speed
Well we are now over the 40,000 article mark including 36,000 + in PubMed alone and we are desperate for clarity on many, many questions but lately, it’s all about the vaccines. We thought we would take a crack at distilling this uber complex field and turn you on to a few cool resources to track. We will start by telling you that we are both personally excited by the prospect of an effective vaccine and we are committed to the cause. Both of us have volunteered for the trials (Cassie is in the queue for the Moderna vaccine discussed below and Len for the Oxford vaccine trial discussed as well). I’d say that we are putting our money where our mouths are for sure just as we have done with our mask /social distancing advocacy.
Vaccine Primer
As all of us know vaccines are complex and the development and approval process lengthy with past efforts generally requiring in the range of 3-8 years of hard core discovery phase work searching for the right target followed by 2-10 years of Phase 1, 2 and 3 trials followed by 1-2 years of regulatory review, so the notion that a pathogen we did not know lived on our planet in January of this year would be dallying with generating an approved and available vaccine by years’ end is literally an effort done at warp speed.
At present, there are over 140 vaccines in active development and over 40 in active clinical trials including a handful in Phase 3. It’s impossible to remember the details of all of these so we think it’s convenient to first keep them in our mind according to the biologic type/category. We both watched a terrific online presentation by Sharon Lewin, the Chair of the Peter Dougherty Institute for Infection and Immunity in Melbourne, which we highly recommend (https://www.clinicaloptions.com/infectious-disease/programs/covid19-resources/medicalminute-updates/mm11?origin=2 ). The figure below is the nicest summary to date from this excellent narrative review on vaccine technology (very thorough but some heavy stepping in the biotech area FYI). A more approachable and informative ongoing (real-time) summary of the New York Times Journal of Medicine (see Covid Corner issue #8) is the Coronavirus Vaccine Tracker ( https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html ). With a bit of basic biology knowledge, you can extrapolate a lot of information from this series and really keep up.
At 30,000 feet – consider the classes.
- Nucleic acid vaccines (12 DNA and 20 or so RNA) have varying delivery methods including oral. These are the new hopes in the vaccine world but be aware that none have been approved for any indication thus far for any infection. These vaccines are delivered in different forms ranging from plasmids to viral vectors and can be replicating or non-replicating. They have the advantage of being scalable for mass production, are robustly immunogenic but limited by some safety concerns (especially DNA vaccines which can insert into the host genome) and questions of durability. RNA vaccines are partially hot and can be delivered in lipid nanoparticles like the Moderna vaccine (see below). A significant concern for RNA vaccines is stability and immunogenicity. Some of these now use nucleoside modified design features to reduce immunogenicity and increase stability and ensure the productivity of the delivered antigen.
- Protein vaccines are the most numerous and generally use the spike structural protein as the antigen and can be modified in numerous ways to maximize its efficiency (at least theoretically). Most of these are produced by recombinant technology from a variety of expression systems (including insect cells from Sanofi) and thus can be readily mass-produced. Some of these proteins are using adjuvants including several partnering with GSK who have extensive experience with adjuvant systems (i.e. Shingrix).
- The third category is viral vector vaccines that use viruses such as a weakened measles virus (a vector recently approved for Ebola vaccine) or adenovirus which are incapable of productive infectivity. The Oxford vaccine described below is a primate-derived adenovirus incapable of active replication. Such virus vaccines often require re-boosting to maintain a productive presence.
- The last category of vaccines uses the SARS CoV2 virus itself either in an inactivated or wakened form similar to measles or polio vaccines. Safety issues abound but at least 7 teams are working on such platforms.
Below are several of the lead candidate vaccines as of this week. Stay tuned for in a month we will see many more with growing data.
Modern mRNA-1273 vaccine – a nucleoside-modified mRNA based vaccine that encodes the perfusion stabilized spike protein. It elicited high levels of neutralizing antibody and Th1 CD4 T cell responses in rhesus macaques (https://www.nejm.org/doi/full/10.1056/NEJMoa2024671), and showed promising results in a phase 1 dose escalation study (https://www.nejm.org/doi/pdf/10.1056/NEJMoa2022483?articleTools=true). A large scale phase 3 study is currently enrolling.
Oxford AZD1222 vaccine (Jenner Institute, Oxford Biomedica, Astrazeneca) – utilizes an attenuated, replication deficient adenovirus vector displaying the SARS-CoV-2 spike protein. It elicited a robust immune response in two animal models and prevented pneumonia in a non-human primate model (https://www.biorxiv.org/content/10.1101/2020.05.13.093195v1) and exhibited acceptable safety profile and induction of humoral and cellular immune responses in a Phase 1/2 trial (https://www.sciencedirect.com/science/article/pii/S0140673620316044?via%3Dihub). Currently enrolling in phase 2/3.
CanSino Adenovirus type 4-Ad5)-vectored vaccine (CanSino Biologis and Beijing Institute of Biotechnology) – employs a full length SARS-CoV-2 spike protein incorporated into a replication-defective adenovirus vector. Promising results from Phase I and II studies lead to a one year approval as a “specially needed drug” for use by the Chinese Military. Details surrounding this approval are murky, as no phase III results have been released, and no mention has been made of how they will use this vaccine, nor whether it will be mandatory or not.
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Leonard H. Calabrese, DO, is the head of the RJ Fasenmyer Center for Clinical Immunology and Vice-Chair of the Department of Rheumatic and Immunologic Diseases at Cleveland Clinic Dr. Calabrese has lectured nationally and internationally on the subjects of immunology, rheumatology, and viral diseases. He is the author of more than 400 published peer-reviewed articles, book chapters, and reviews. @LCalabreseDO
Cassandra Calabrese, DO, is a staff physician in the Department of Rheumatic and Immunologic Diseases and the Department of Infectious Diseases at Cleveland Clinic and directs the combined Rheumatology-Infectious Disease training program. She also directs the Clinic for immune-related adverse events form cancer immunotherapy within the department of Rheumatic and Immunologic Diseases. @CCalabreseDO