Investigational Therapeutics & Vaccine Development

Investigational Therapeutics

In this section we will build off fundamental SARS-CoV-2 virology and COVID-19 pathogenesis discussed in section 1 to explore the scientific basis of therapeutics and vaccines. We will discuss general approaches to therapies and vaccines but we will not be providing most up-to-date information about specific therapies. For that level of information, we highly suggest referencing The New York Times COVID-19 drug and vaccine trackers which are updated daily.

Thought Question:

• Based on what you know about SARS-CoV-2 viral structure and pathogenesis, what kinds of drugs do we already have on the market that could have efficacy in treating COVID-19?

Drug approval process

The FDA (US Food and Drug Administration) is responsible for approving new drugs. The Center for Drug Evaluation and Research (CDER) receives applications for new medications and evaluates the evidence that the new drug is safe and effective (FDA website).

In order to test the new compound, the company or group developing the drug must perform preclinical studies, usually on cells and experimental animals, to understand how the drug is likely to work and the safety profile. They then submit data from preclinical studies to the FDA to obtain an investigational new drug (IND) approval. Next, they test the medication in phase 1, 2 and 3 studies. Phase 1 studies evaluate the drug’s safety in humans by giving a small dose to a small group of people, observing them for side effects, and then gradually scaling up the dose. Phase 2 studies look for efficacy based on markers of disease in a somewhat larger group of people. Phase 3 studies compare the medication to whatever is currently available, which may be the standard of care or placebo, and are done in a large enough group of people to statistically evaluate pre-determined outcomes (Cancer.org, Types and Phases of Clinical Trials). During the clinical trial phase, access to INDs is only available as part of a clinical trial, with exceptions noted below. Evidence from these studies is submitted to the FDA as part of a New Drug Application (FDA website).

In states of emergency, the FDA can authorize treatments for life-threatening conditions when there are no adequate, approved and available alternatives using a method called Emergency Use Authorization (EUA). The secretary of Health and Human Services authorized EUAs for COVID-19 effective March 27, 2020 (FDA website); these approvals will be valid until the state of emergency ends. The EUA is made given the best available evidence weighing risks and benefits in order to make products available to the public in a timely manner, and may be revoked as further evidence becomes available. Please see this website for an updated list of EUAs for vaccines, therapeutics, and medical devices.

Other pathways for access to medications for a new condition like COVID-19 include expanded access and off-label use (FDA website). Expanded access, also known as compassionate use, allows people with a serious or life-threatening condition to access investigational new drugs outside of a clinical trial. Expanded access has been used frequently for convalescent plasma, which made it harder to evaluate the efficacy of the treatment. Off-label use allows providers to prescribe an FDA-approved medication for another indication than the original one it was approved for. This mechanism has been used for many medications like hydroxychloroquine that were approved by the FDA for treatment and prevention of malaria and treatment of certain autoimmune diseases.

Thought Question:

• What are the advantages and disadvantages to an individual patient to receiving a drug outside of a clinical trial through expanded access or off-label use? What about to society?

Approaches

Some medications target the virus, while others target the immune response to the virus.

Of antivirals, some are small molecules which inhibit viral processes. For example, remdesivir is a nucleotide analog which interferes with replication of SARS-CoV-2 by causing premature termination of RNA made by the viral RNA-dependent RNA polymerase. Other virally-directed medications are biologic drugs that use antibodies to block viral entry, like the monoclonal antibodies bamlanivimab, etesevimab, casirivimab and imdevimab. These types of medications can lose efficacy as SARS-CoV-2 evolves, but are less likely to interfere with other homeostatic processes.

Anti-inflammatory drugs include corticosteroid hormones like dexamethasone, small molecules like baricitinib, and larger proteins like tocilizumab. These medications inhibit the inflammatory response which is responsible for many of the symptoms of COVID-19 by targeting inflammatory signaling. The drugs that target the immune response to the virus are more useful later in the course of disease when more symptoms are due to the immune response rather than the virus itself.

For more information on particular medications, please visit these resources:

• The New York Times COVID-19 drug and vaccine trackers

• We have made concept videos for medical professionals on leading antiviral and immune therapies for COVID-19, including mechanism, trial data and outlook:

• • Medications for COVID-19: Antivirals (Part 1)

  • Medications for COVID-19: Immune Therapies (Part 2)

  • Therapeutic summary image

Vaccines

Thought Questions:

• How do we balance the need to quickly develop and distribute existing vaccines vs. the ethical considerations of testing new vaccines to make sure they are safe and effective?

Timing

Vaccines are used in healthy individuals to prevent the development of future illness, as well as to attenuate the duration and severity of symptoms in those who do develop illness in the future. Prior to a vaccine’s introduction on the market, scientists must go through the following steps: (Review: Vaccine Testing and Approval Process (CDC) and video (CNBC)

• Phase 1 trials with small numbers of healthy patients will first strive to demonstrate that the vaccine is safe, void of adverse side effects, and establish an acceptable dosage. This is especially important given that vaccines are given to healthy individuals, rather than sick individuals, and must reach a greater threshold for safety.

• Phase 2 trials enroll a larger group of individuals and aim to demonstrate the vaccine is effective in preventing the symptoms or disease under investigation. The subjects enrolled tend to be people that are considered to benefit most from a new treatment (i.e. elderly, persons with comorbid conditions).

• Upon successful completion of the prior stage, phase 3 trials enrolling even more patients will seek to show continued safety and efficacy. Typically Phase 3 trials are conducted in an area where a pathogen is endemic and the frequency of infection in the vaccinated and control groups are compared and efficacy thus determined. However in this outbreak some ethicists have supported human challenge studies in well informed volunteers, in which one arm of the study will involve volunteers receiving a deliberate vaccine challenge.This issue is currently being debated with some civil society organizations pushing for this approach (https://www.1daysooner.org/).

• After a phase 3 trial, the vaccine is generally approved and available to the general public, though formal phase 4 trials are encouraged (but not usually formally required) to assess for longer-term safety and efficacy. The safety of the vaccine should continue to be surveilled after its rollout to the public as well. Two examples of this in the US include the Vaccine Adverse Event Reporting System (VAERS), which accepts reports of complications for any vaccine, and the opt-in V-SAFE program, which surveys vaccine recipients multiple times after vaccination against SARS-CoV-2

Approaches

As clinical trials for COVID-19 vaccines continue and multiple vaccines are administered, the choice of viral component to be used as a basis for developing immunity is an important consideration. In general, previous vaccine strategies for SARS & MERS have targeted the S protein, since it has been shown to play a role in inducing protective immunity by eliciting the production of neutralizing-antibodies and T-cell responses (Keng et al. 2005; Zhou et al. 2004; Bukreyev et al. 2004). Based on the function of this protein, it is also an attractive target because immunity against this protein could block virus binding, impair membrane fusion or neutralize infection.The use of an inactivated SARS-CoV-2 vaccine resulted in the generation of neutralizing antibodies and the protection of immunized macaques from SARS-CoC-2 rechallenge without any evidence of disease enhancement (Gao et al., Science 2020). There are many different types of vaccines in the modern era, including whole pathogen vaccines (either killed/inactivated or live attenuated), subunit vaccines, mRNA vaccines, and DNA vaccines (Vaccine Types | NIH). Vaccines previously developed for SARS and MERS have informed the approach to SARS-CoV-2 vaccine development. Different approaches are detailed below and are also described more broadly in this NYT article:

Whole pathogen vaccines require the pathogen to be grown in the laboratory, where they can then either be killed with chemicals, heat, or radiation (to make a killed/inactivated vaccine) or weakened (to make a live attenuated vaccine), and then incorporated into the vaccine. Yet another approach that has been used for many live viral vaccines is codon deoptimisation of the genetic material of a virus to make it less virulent. The use of non-preferred codons can markedly reduce viral protein expression. This approach has been used for a SARS-CoV-2 vaccine as well.

Hybrid vaccines incorporate part of the pathogen of interest’s genetic material into that of a harmless pathogen, often an adenovirus, to create a “chimeric pathogen”, which can be used to stimulate the immune system. Adenoviruses like Adenovirus 26 can enter many different human cells at the site of infection and thus serve as potent immunogens.

Subunit vaccines utilize laboratory techniques to create the components (i.e. antigens) of the pathogen that best stimulate the immune system and incorporate these into a vaccine.

mRNA vaccines are developed by identifying the genetic sequence of the pathogen and then determining which sequences code important, unique components (antigens) of the pathogen. mRNAs for these genetic sequences are synthesized, altered to enhance RNA stability and translatability by addition of a 5’cap and a long polyA tail, altering 5’ and 3’ UTRs and changing codon usage. mRNA vaccines can be rapidly designed and manufactured and mRNAs for multiple antigens can be easily combined into a single vaccine. mRNAs can be linked to alphavirus RNA sequences to make them self-replicating and this enhances the expression of the antigen/s encoded. Once the vaccine is introduced into a recipient, the recipient's cells will use the mRNAs to make the corresponding proteins, which will then stimulate the immune system. These designs have been shown to have greater stability and protein translation efficiency which translates into a more robust immune response.

DNA vaccines work similarly to RNA vaccines. Instead of RNA, a cDNA is injected usually into the vaccine recipient’s muscle tissue. Some of the recipient's dendritic cells likely take up the cDNA that is then transcribed and translated to generate the relevant antigen. These cells migrate to draining lymph nodes and thus initiate an immune response.

Nanoparticle vaccines utilize an understanding of synthetic biology to create nanoparticles out of proteins that are then studded with pathogenic components (antigens) for a pathogen. The idea is that while the underlying nanoparticle could stay consistent from vaccine to vaccine, the antigens could be switched out easily and interchangeably, allowing for rapid vaccine development. This could be especially important if the SARS-CoV-2 virus, as is feared, becomes a yearly illness like influenza (Begley et al. 2020) and if nanoparticle vaccines developed do not induce durable immune responses.

Vaccines also commonly have adjuvants, which are used in order to increase the immune system’s response to a vaccine and thus develop a more effective immunity to a pathogen in the future. They have been used safely in vaccines for decades (CDC | Adjuvants help vaccines work better).

Clinical Vaccine Trials

Many pharmaceutical companies and governments are currently in the process of developing SARS-CoV-2 vaccines, and strategies with all of the above vaccine types are being utilized (Pang et al., JCM 2020). The speed at which each type of vaccine can be developed can vary, with mRNA/DNA vaccine development being more rapid and subunit development more slow (read Lurie et al. NEJM 2020 to learn more). A list of vaccines under clinical and preclinical development is compiled and updated by WHO. The NYT also has an easy to follow vaccine tracker.

Summary

Knowledge of COVID-19 pathogenesis is emerging at a lightning pace, and the evidence-basis underpinning our diagnosis and treatment guidelines are constantly under review. We as medical students and global citizens are living and learning through a formative time. Now, more than ever, it is critical for the scientific and medical community to collaborate, to innovate, and to push the frontiers of our understanding.

__________________________________________________________________

We hope that this module highlighted the frontier of basic science and translational research on COVID-19. It provides a conceptual grounding on COVID-19 pathophysiology and how this relates to evolving diagnosis, treatment, and prevention efforts to prepare you for the impacts that this disease has on society, the government, and our healthcare systems.

We welcome your feedback on this module and on the curriculum overall. Please share it here.