Investigational Therapeutics & Vaccine Development

This section will build off the fundamental SARS-CoV-2 virology and potential mechanisms of COVID-19 pathogenesis to explore the scientific basis of potential therapeutics and vaccines. In addition, we will provide information on clinical trials and approval of COVID-19 therapeutics and vaccine development. As best as possible, we will maintain an update of in vitro, animal based, and clinical studies of therapeutic effectiveness of investigational drugs, vaccines and therapies in this section.

Thought Questions:

  • 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?

  • Who will most benefit from investigational therapeutics? From a vaccine?

Investigational Therapeutics

There are currently no FDA approved treatments for any coronavirus in the US; this includes SARS & MERS. However, on 3/29/2020, the FDA issued emergency use authorization (EUA) for the antimalarials hydroxychloroquine and chloroquine (subsequently revoked), and on 5/1/2020, the FDA issued a second EUA for the novel antiviral drug remdesivir. EUAs are issued when the FDA determines that the known and potential benefits of a drug outweigh the known and potential risks of the product and that there are no alternatives available. This allows physicians to prescribe these drugs for hospitalized patients when appropriate, but does not mean that the drugs have demonstrated efficacy through clinical trials or that the drug has received FDA approval (Rome and Avorn, NEJM 2020). This section will build off the fundamental SARS-CoV-2 virology and potential mechanisms of COVID-19 pathogenesis to explore the scientific basis of potential therapeutics and vaccines. We will highlight important pre-clinical in vitro and in vivo data. Additionally,we will discuss the relevance of recent clinical trials investigating drug and vaccine efficacy.

Other Resources:

Remdesivir

Current Prescribed Use: Remdesivir was originally developed by Gilead Sciences as a novel antiviral for Ebola and Marburg virus infections (Mulangu et al., NEJM 2020). However, it is not currently used for Ebola or Marburg due to clinical inferiority compared to other drugs. It acquired EUA from the FDA on 5/1/2020.

Mechanism of Action: Nucleotide analog; causes premature termination of the viral strand made by the viral RNA-dependent RNA polymerase.

In vitro/in vivo work: Both MERS-CoV and SARS-CoV-1 are inhibited by remdesivir in multiple in vitro systems and activity against SARS-CoV-2 infectivity has been reported in vitro at micromolar levels (Wang et al., Cell Res. 2020). Treatment with remdesivir in In mouse and non-human primate models of SARS and MERS, treatment led to significantly reduced lung viral load and improved respiratory function (Sheahan et al., Sci Trans Med. 2017). Similarly, in rhesus macaques infected with SARS-CoV-2, early treatment with remdesivir led to improved clinical course, reduced BAL viral titers and reduced lung viral load (Williamson et al., bioRxiv 2020). In the first SARS-CoV-2 in vivo remdesivir study, clinical benefit, reduced BAL viral titers, and reduced lung viral load were demonstrated in rhesus macaques initiated on remdesivir early during infection (Williamson et al., bioRxiv 2020).

Clinical Results in COVID19: Interest in remdesivir gained traction after its compassionate use helped treat one of the first patients in the United States in critical illness (Holsue et al., NEJM 2020). In a multicenter case series of the compassionate use of remdesivir for up to 10 days in 53 patients with severe COVID-19 and hypoxia, 68% had clinical improvement (discharge or decreased requirement for oxygen support) and 13% died. Out of the 30 intubated patients, 57% (17 patients) were extubated. Elevated liver enzymes was the most frequently reported adverse event(23%)(Grein et al., NEJM 2020).

Initial results from a comparison of a 5 to a 10 day regimen in patients with severe disease suggested no difference in outcomes (clinical recovery, discharge, or death) between the lengths of regimens. However, conclusions about treatment benefits are limited as there was no control group (Gilead 2020). Ten hospitals in Hubei, China conducted the first multi-center, randomized, double-blind, placebo controlled study of remdesivir. While mortality outcomes are similar between remdesivir and placebo arms, time to symptom resolvement was shorter in the remdesivir treated group. The trial was underpowered (only enrolled 52% of target sample) due to the declining incidence of COVID-19 in Hubei (Wang et al, Lancet 2020).

On April 29, initial findings from the NIAID Adaptive COVID-19 Treatment Trial, a Phase 3 double-blind placebo controlled RCT (NCT04280705), were released. In more than 1000 patients with moderate to severe disease at 68 sites, time to recovery was 11 days in the remdesivir arm versus 15 days in the placebo arm (NIH News Releases 2020). No significant difference in mortality was observed (with a trend towards mortality benefit; mortality rates of 8% in the remdesivir arm and 11.6% in the placebo arm, p=.059).

The ACTT-1 trial demonstrated through a double-blind, randomized, placebo-controlled trial that remdesivir treatment resulted in decreased hospital stay (15 vs 11 days) (Beigel et al, NEJM 2020) in 1000 patients hospitalized for COVID19. The trial additionally identified a trend towards decreased mortality with remdesivir, but this did not reach statistical significance.

In response to the initial results of the NIAID Adaptive Trial, on May 1 the FDA issued an EUA authorizing the use of remdesivir in severe disease (SpO2 ≤ 94% on room air, requiring supplemental oxygen, mechanical ventilation, or ECMO; FDA Letter of Authorization 2020). Because the optimal dosing and duration of treatment is unknown, preliminarily a 10-day course is suggested for patients requiring mechanical ventilation and/or ECMO. The US government will coordinate the distribution and allocation of the current supply of remdesivir based on need (Gilead News Release 2020).

Ongoing Clinical Trials: Many randomized trials investigating remdesivir are still ongoing globally and in the United States.

Chloroquine and Hydroxychloroquine

Current Prescribed Use: Anti-malarial; Hydroxychloroquine also used in treatment of autoimmune diseases such as lupus and rheumatoid arthritis due to its immunomodulatory effects

Mechanism of Action: Not fully understood. Leading hypotheses include the inhibition of viral fusion to the endosomal cell membrane through pH modulation and limiting the glycosylation of cellular receptors on the viral membrane.

In vitro/In vivo work: Since the 1960s, the antiviral activity of chloroquine has been noted in vitro. Cell culture inhibition of viral replication was noted for SARS-CoV-1 and MERS-CoV. Also has been shown to inhibit SARS-CoV-2 viral entry and viral replication in vitro at micromolar levels (Yao et al Clin Infect Dis 2020).

Clinical Results in COVID-19: The data supporting the use of hydroxychloroquine and chloroquine for the treatment of COVID-19 are mixed, with insufficient results to define a clear benefit and continued concerns over drug toxicity. The earliest results from China reported a shorter disease course in patients treated with chloroquine across 10 hospitals (Gao et al., BioScience Trends 2020). Subsequently, in a small non-randomized French study of hydroxychloroquine and azithromycin, researchers reported a faster decrease in viral load by nasal swab (Gautret et al. 2020), however methodologic issues have cast doubt on the study’s results. Subsequent studies have not observed a similar benefit of hydroxychloroquine (Mahevas et al., MedRxiv 2020; Molina et al., Med Mal Infect. 2020). While a randomized trial of 62 mild COVID-19 patients without hypoxia in Wuhan concluded that addition of hydroxychloroquine to standard of care led to a 1-day faster time to improvement of symptoms (fever, cough) and chest imaging findings, and possibly lower likelihood of disease progression, adverse events were not recorded (Chen et al. medRxiv 2020). In mid-April, an open-label multi-center Chinese RCT of 150 hospitalized COVID-19 patients found no significant difference in likelihood of viral RNA clearance, and no significant difference in symptom resolution over 28 days, for hydroxychloroquine compared to standard of care. The researchers did find hydroxychloroquine-treated patients had a significantly lower CRP and an insignificant trend towards faster resolution of lymphopenia, though these lab findings did not translate to clinically meaningful results. Hydroxychloroquine-treated patients also had a higher adverse event rate of 30% compared to 8% in the standard of care arm (Tang et al., BMJ 2020). In a retrospective cohort study of 1438 hospitalized patients in New York State, treatment with hydroxychloroquine, azithromycin, or both were not associated with lower mortality (Rosenberg et al JAMA 2020). Despite having inconclusive results, on 3/29/20, the FDA issued an EUA for chloroquine and hydroxychloroquine, allowing physicians to prescribe these drugs for hospitalized patients when deemed appropriate (and outside of a clinical trial). As a result, hydroxychloroquine, alone or in combination with azithromycin, has been widely used in the US. However, caution regarding drug toxicity (particularly QT prolongation and cardiomyopathy) is advised by the American College of Cardiology. In fact, one trial comparing azithromycin in combination with two doses of chloroquine halted the high-dose arm of the study after an interim analysis revealed a trend towards greater mortality and QT prolongation in the high-dose group (Borba et al, JAMA Netw Open 2020). In addition, in a retrospective analysis of 368 US VA patients on hydroxychloroquine alone or in combination with azithromycin, both exposures were not associated with a reduced risk of ventilation requirements, and those treated with hydroxychloroquine alone had an overall increase in mortality (Magagnoli et al., medRxiv 2020). To this effect, on 4/24/20, the FDA issued a drug safety communication highlighting the risk of QT prolongation, particularly in patients with renal disease and in combination with other medications that prolong the QT interval, including azithromycin. While still available under the EUA, the FDA recommends enrollment in a clinical trial for consideration of use.

The first post-exposure prophylaxis trial of hydroxychloroquine, a randomized, double-blind, placebo controlled trial, did not demonstrate prevention of COVID-19 using hydroxychloroquine prophylaxis within 4 days of high- or medium- risk exposure (Boulware et al NEJM 2020). High risk was defined as “household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield” while medium risk persons had a face mask but no eye shield during exposure. Concerns over hydroxychloroquine toxicity led the FDA to issue a drug safety communication regarding the drug on 4/24/2020.

Ongoing Clinical Trials: Many clinical trials are underway (Cortegiani et al., J Crit Care 2020), including pre- and post-exposure prophylaxis trials in healthcare workers (COPCOV trial, PrEP_COVID trial). In March 2020, the WHO launched an open-label, multicenter, randomized, adaptive SOLIDARITY trial, which includes hydroxychloroquine/ chloroquine as a treatment arm (Science Magazine, 2020). INSERM, the French biomedical research agency, is coordinating a European add-on study of the same treatments called DISCOVERY (ClinicalTrials.gov 2020).

Thought questions:

  • As demonstrated by the mixed evidence from the above hydroxychloroquine studies, the methodology of a clinical trial can majorly impact the validity of its outcomes. If you were a clinical investigator, what kind of study would you design to investigate the effects of hydroxychloroquine on COVID-19 patients? What would be your inclusion and exclusion criteria? What would be your primary and secondary outcomes?

Lopinavir/Ritonavir

Current Prescribed Use Prevention of HIV

Mechanism of Action Lopinavir inhibits HIV-1 protease, inhibiting the cleavage of GAG-POL polyprotein precursors into their functional products. Ritonavir increases plasma concentrations of lopinavir by inhibiting its metabolism by CYP3A. Of note, they are the wrong class of protease inhibitors for coronavirus proteases (cysteine protease instead of serine).

In vitro/in vivo work Treatment with Lopinavir/Ritonavir was associated with lower rates of death and ARDS in retrospective studies of SARS-CoV-1.

Clinical Results in COVID-19 In an early case series in Singapore, 3 out of 5 patients treated with lopinavir/ritonavir exhibited improvements in fever and need for supplemental oxygen (Young et al., JAMA 2020).

Subsequently, a randomized controlled open label trial in 199 patients in Wuhan, China with enrollment from January 18 - February 3, had no observed benefit of lopinavir/ritonavir over standard of care in terms of viral load, time to clinical improvement, or mortality. However, there was a trend towards faster improvement in those who received the medication early in their disease course (Cao et al., NEJM 2020).

Ongoing Clinical Trials Multiple trials involving lopinavir/ritonavir in comparison to and/or in combination with umifenovir, ribavirin, interferon-beta, umifenovir, hydroxychloroquine, and additional protease inhibitors are ongoing. The SOLIDARITY and DISCOVERY trials include lopinavir/ritonavir alone and in combination with interferon-beta as treatment arms.

Favipiravir

Current Prescribed Use Catarrhal (respiratory tract mucous membrane inflammation), approved for influenza A resistant to neuraminidase inhibitors in Japan (Hayden and Shindo, Curr Opin Infect Dis, 2019).

Mechanism of Action Not fully understood, potentially a selective inhibitor of viral RNA-dependent RNA polymerase.

In vitro/in vivo work Activity against a broad array of RNA viruses in vitro (Furuta et al Proc Jpn Acad Ser B Phys Biol Sci 2017); in vitro activity also demonstrated against SARS-CoV-2 (Wang et al Cell Res 2020).

Clinical Results in COVID-19 A multicenter, open-label trial of favipiravir versus umifenovir (Arbidol, an influenza membrane fusion inhibitor, see below) demonstrated improved clinical recovery rate at day 7 in moderately ill patients but not in mildly or severely ill patients (Chen et al. medRxiv 2020). In a small open-label non-randomized trial vs. historical controls with lopinavir/ritonavir, favipravir had earlier time to viral clearance in mild-moderate disease (median 4 vs. 11 days, Cai et al., Engineering 2020).

Ongoing Clinical Trials Several investigations are ongoing and/or recruiting, particularly in China where investigators are evaluating the use of favipiravir in combination with tocilizumab and in several Massacusetts hospitals.

Umifenovir (Arbidol)

Current Prescribed Use Umifenovir (also called arbidol) is approved in Russia and China for influenza treatment and prophylaxis (Blaising et al, Antiviral Res, 2014).

Mechanism of Action Targets the S protein/ACE2 interaction and inhibits membrane fusion of the viral envelope (Rameshwar and Wilson, PNAS 2017).

In vitro/in vivo work Antiviral activity demonstrated against SARS-CoV-1 (Khamitov et al., Vopr Virusol 2008).

Clinical Results in COVID-19 Treatment with umifenovir (median duration 9 days) was associated with lower mortality rates (0% [0/36] vs 16% [5/31]) compared to control in a non-randomized study of 67 patients (Wang et al., Clin Inf Dis 2020).

Ongoing Clinical Trials Randomized clinical trials investigating umifenovir are underway; none as of yet in the United States.

Camostat Mesylate

Current Prescribed Use Approved in Japan and South Korea for the treatment of pancreatitis.

Mechanism of Action Inhibits host serine protease TMPRSS2, required for S protein cleavage and cell entry.

In vitro/in vivo work Demonstrated to inhibit SARS-CoV-2 cell entry in vitro (Hauffman et al., Cell 2020).

Ongoing Clinical Trials A Danish randomized, placebo-controlled trial will investigate camostat mesylate in COVID-19 patients at the maximum dose currently approved for pancreatitis in Japan (NCT04321096).

Interleukin-6/IL6R Inhibition (tocilizumab, sarilumab, siltuximab)

Current Prescribed Use: Immunosuppressive drugs used to treat moderate or severe rheumatoid arthritis

Mechanism of Action: Humanized monoclonal antibody against the interleukin-6 (IL-6) receptor (Tocilizumab and Sarilumab) or IL-6 (Siltuximab), mitigating the cytokine storm hypothesized to correlate with COVID-19 disease severity (Liu et al., MedRxiv. 2020).

In vitro/in vivo work: None at present. Interest in use generated solely from international human observational data during the SARS-CoV-2 outbreak. Clinical Results in COVID-19: In March 2020, Xu et al. described that in 15 out of 20 patients, treatment with tocilizumab showed a decrease in oxygen requirement and temperature, prompting China’s National Health Commission to approve the use of tocilizumab to treat patients with severe or critical disease (Xu et al., ChinXiv 2020). Other case reports have also described good outcomes with tocilizumab (Luo et al., J Med Virol. 2020, Michot et al., Ann Oncol. 2020). As of yet, there are no randomized controlled trial data for IL-6 inhibition.

Ongoing Clinical Trials: IL-6R or IL-6 inhibition through tocilizumab, sarilumab, and siltuximab is being evaluated in multiple clinical trials. A Phase 3 trial of sarilumab expects results by June (Regeneron Press Release 2020).

In Vitro Pipeline

β-D-N4-hydroxycytidine (NHC, EIDD-2801)

Current Prescribed Use: Investigational drug, not presently in use

Mechanism of Action: Nucleoside analog; induces lethal viral mutagenesis, a process by which virions have a high mutation burden that impairs replication

In vitro/in vivo work: Dose dependent antiviral activity against MERS-Cov and SARS-CoV-2 in human lung epithelial cell line and against SARS-CoV-2, MERS-CoV and SARS-CoV in primary human airway epithelial cells with no indication of cytotoxicity. (Sheahan et al., Sci Trans Med 2020).

EIDD-2801 reduces viral loads, prevents body weight loss and decreases lung hemorrhage in SARS-CoV infected mice, although the extent of benefit is dependent on time post infection that therapeutic dose is given (Sheahan et al., Sci Trans Med 2020).

Clinical Results in COVID-19 : Not being investigated clinically.

Passive antibody transfer

History of convalescent sera The role of our immune system is to develop “memory” against foreign pathogens so that once exposed a second time to said pathogens, neutralizing antibodies are used to quickly eradicate an impending infection. With this understanding, physicians and scientists have long been interested in the transfusion of human convalescent sera (that which contains neutralizing antibodies from a recovered patient) to treat infection or serve as prophylaxis immediately following exposure (Casadevall and Scharff 1995). Passive antibody transfer tends to be more effective for prophylaxis than for treating systemic infection, and therefore should be given shortly after symptom onset. While we don’t fully understand how temporality of administration affects efficacy, it is thought that smaller inoculums may be more manageable for neutralization than systemic infection, or that the transferred antibodies modulate the receiver’s inflammatory response which is more easily done at earlier stages of infection.

If interested in learning more about previous uses of convalescent sera for treatment of viral infections please read:

Poliomyelitis: Park 1932 Measles: Gallagher 1935; Park and Freeman 1926 Ebola: Sahr et al. 2017 Influenza: Luke et al. 2006; Hung et al. 2011

A proposed convalescent sera therapy protocol in COVID-19 from Casadevall and Pirofski 2020. Serum collected from recovered COVID-19 patients that have high titers of neutralizing antibody would be administered prophylactically to high-risk individuals (elderly, patients with comorbid conditions, health care workers or individuals with known exposure) or to patients with severe disease to dampen severity of symptoms and mortality.

During the epidemics of SARS and MERS, high mortality and dearth of effective treatment options led to use of convalescent serum (Cheng et al. 2005). A recent study reported that sera collected from confirmed positive SARS-CoV-2 patients have the ability to neutralize SARS-CoV-2 in an in vitro plaque assay (Zhou et al. 2020).

Clinical Results In COVID-19 In August 2020, the FDA issued emergency use authorization (EUA) for convalescent plasma as a treatment for hospitalized COVID-19 patients. A preprint study of 35,322 COVID-19 patients transfused with convalescent plasma showed that patients treated within 3 days of COVID-19 diagnosis exhibited a reduction in mortality: 8.7% seven-day mortality rate compared to 11.9% for patients transfused 4 or more days after diagnosis (Joyner et al; preprint medRxIV 2020 NCT04338360). The study also showed that treatment using convalescent plasma with higher IgG antibody levels (>18.45 S/Co) significantly reduced mortality compared to transfusions with low IgG antibody levels (<4.62 S/Co) (8.9% compared to 13.7%). However, it is important to note that higher IgG levels do not necessarily imply virus-specific antibodies and the possibility that the benefits represent an IVIg-like effect cannot be excluded. Given that this was not a randomized clinical trial (RCT) or have a control arm, both the authors and FDA discuss that additional RCTs are needed. The American Red Cross is helping to find appropriate donors and distribute convalescent plasma across the United States (FDA News Release 2020).

Other non-randomized, not well-controlled studies also suggest an incremental benefit from convalescent plasma. A preprint pilot study in 10 severely ill patients performed in China revealed that transfusion was well tolerated and that, in 7/10 patients, viral load was undetectable one week after treatment (Duan et al;, preprint medRxIV 2020). Another case-series study in China demonstrated improvement in five patients with severe COVID-19 after treatment with convalescent plasma (Shen et al. JAMA 2020).

Several convalescent plasma approaches against SARS-CoV-2 are in development:

  • Regeneron Pharmaceuticals: Using antibody-generating mice exposed to a harmless analogue of SARS-CoV-2, they aim to find a potent antibody that provides immunity in these mice to SARS-CoV-2. The hope is that these antibodies can also be given to humans to fight the SARS-CoV-2 virus. During the Ebola outbreak in 2015, Regeneron Pharmaceuticals used a similar approach to develop a treatment for Ebola that significantly improved the survival rate.

  • Vir Biotechnology: By isolating antibodies from patients who survived SARS (which is a coronavirus related to the novel SARS-CoV-2 coronavirus), they hope to determine whether these antibodies against SARS provide some benefit against this new related SARS-CoV-2 virus.

Thought questions:

  • What are the pros and cons of sharing preprint data (e.g. non peer-reviewed data published on medRxiv or bioRxiv) for clinical trial results

  • Which therapies (if any) do you think are most promising so far?

Vaccines

Thought Questions:

  • How do we balance the need to quickly develop and distribute a vaccine vs. the ethical considerations of testing the vaccine to make sure it is safe and effective?

  • How will a potential vaccine be shared with the world, and who should receive the vaccine first in instances where there is a limited supply (i.e. rationing)?

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. Most sources are indicating that a COVID-19 vaccine will not be ready for public use until at least 1 year from now (MGH Grand Rounds 3/12/2020). Prior to a vaccine’s introduction on the market, scientists not only need to identify specific markers of the virus (antigens) to be incorporated into a vaccine used to stimulate the immune system, but will also need to undergo the entire clinical trial process to demonstrate that the vaccine is both safe and effective. (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 being debated but the likelihood that such studies might be conducted in the fall of 2020, has greatly increased.

  • After a phase 3 trial, the vaccine is generally approved and available to the general public, though formal phase 4 trials are encouraged (but usually not formally required) to assess for longer-term safety and efficacy.

Approaches

While some clinical trials for COVID-19 vaccines are already underway in the US and abroad, what the medical and scientific community must consider is which viral component will be used as a basis for developing immunity. 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:

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

***This section is undergoing major changes/additions, please bear with us while we update***

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).

Vaccine Type

Target

Developer

Phase

Updates

Genetic

mRNA-1273

Moderna + NIH

3

mRNA-1273 demonstrated efficacy in a pre-clincial trial with non-human primates

Phase 1 results demonstrated anti-SARS-CoV-2 responses in all participants with no safety concerns. 8/11/2020 - US govt offered 1.5 billion to Moderna in exchange for 100 million doses if effective

Genetic

mRNA encoding glycoprotein receptor-binding domain ‘BNT162b1’

Biontech, Pfizer, FosunPharma

2/3

Phase 1/2 results demonstrated dose-dependent increases in RBD-IgG and also found SARS-CoV-2 neutralizing titers that exceeded that of COVID-19 + patient sera

Genetic

DNA

Zydus

2

Genetic

RNA

Imperial College London, Morningside

1/2

Genetic

DNA

AnGes, Osaka University, Takara Bio

1/2

Genetic

Arcturus therapeutics, Duke-NUS Medical

1/2

Genetic

Inovio

1

Genetic

Urevac

1

Genetic

DNA

Genexine

1

Genetic

Academy of MIlitary Medical Sciences, Suzhou Abogen Biosciences and Walvax Biotechnology

1

Genetic

Sanofi, Translate Bio

Pre-Clinical

Viral Vector

Nonreplicating adenovirus type 5 vector (chimeric)

CanSino Biological Inc.

3

6/25/2020 Approved for limited use in the Chinese military

Viral Vector

Chimpanzee adenovirus ChAdOx1

AstraZeneca, University of Oxford

2/3

9/8/20 Trial halted due to transverse myelitis complication in study volunteer (unclear at this time if this was related to the vaccine - investigation ongoing)

Viral Vector

Nonreplicating Ad26

Johnson & Johnson (Janssen), BIDMC

1/2

Viral Vector

Ad5 and Ad26 + SARS-CoV-2 gene

Gamaleya Research Institute

1

Viral Vector

Reithera, Lazzaro Spallanzani Ntl Inst for ID

1

Viral Vector

Merck, Themis Bioscience, Institut Pasteur

1

Viral Vector

Merck, IAVI

Pre-Clinical

Viral Vector

AAV

Novartis, Mass Eye & Ear

Pre-Clinical

Viral Vector

Adenovirus

Vaxart

Pre-Clinical

Protein

Viral proteins + adjuvant

Anhui Zhifei Longcom, Chinese Academy of Medical Sciences

2

Protein

Novavax

1/2

Protein

Viral proteins + adjuvant

Clover Biopharmaceuticals, GSK, Dynavax

1

Protein

Viral proteins + adjuvant

Vaxine

1

Protein

Tobacco-plant mediated production of virus-like protein

Medicago, GSK, Dynavax

1

Protein

Viral proteins + adjuvant (CSL)

The University of Queensland, CSL

1

Protein

Tobacco-plant mediated production of virus-like protein

Kentucky BioProcessing

1

Whole Virus

Inactivated virus

Wuhan Institute of Biological Products

3

Whole Virus

Inactivated virus

Sinopharm

3

Whole Virus

Inactivated virus

Sinovac Biotech

3

Whole Virus

Inactivated virus

Chinese Academy of Medical Sciences

2

Whole Virus

Inactivated virus

Indian Council of Medical Research, Natl Institute of Virology, Bharat Biotech

1/2

Repurposed

Bacillus Calmette-Guerin (BCG) vaccine

Murdoch Children’s Research Institute + others

3

Based on limited evidence, it is hypothesized that the BCG vaccine, first developed in the early 20th century to prevent tuberculosis, may stimulate the immune system in a way that reduces the risk of any given infection. These findings have mainly been observational or in very limited clinical trials. It is thought that the BCG vaccine may upregulate activation of the innate immune system’s macrophages, neutrophils, and natural killer (NK) cells, inducing heightened immune responses against all pathogens.

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.

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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.