Innovative approaches to COVID-19 medical countermeasure development

Abstract

Background

The COVID-19 pandemic, while unfortunately notable for immense strain and death throughout the world, has also shown great promise in the development of medical countermeasures. As the global scientific community shifted almost entirely towards vaccines, diagnostics and therapeutics, new trial designs most significantly adaptive platform trials, began to be used with greater speed and broader reach. These designs allowed for deploying and investigating new therapeutics, repurposing currently existing therapeutics and flexibly removing or adding additional medications as data appeared in real-time. Moreover, public–private sector partnering occurred at a level not seen before, contributing greatly to the rapid development and deployment of vaccines.

Objectives

To provide a brief overview of the advances in preventative and therapeutic medical countermeasure development for COVID-19.

Methods

A narrative review of relevant major medical countermeasure trials was conducted using the date range February 2020–December 2022, representing the period of greatest productivity in research to investigate COVID-19.

Results

Among the most influential trial designs are the adaptive platform designs, which have been applied to the development of initial COVID-19 antivirals, monoclonal antibodies, repurposing of existing immunomodulatory therapy and assisted in the disproof of ineffective medical therapies. Some of the most prominent examples include the REMAP-CAP, RECOVERY and TOGETHER trials.

Conclusions

Adaptive platform trial designs hold great promise for utility in future pandemics and mass casualty events. Additionally, public–private sectoring is essential for rapid medical countermeasure development and should be further enhanced for future biopreparedness.

At the close of 2019, the virus that would go on to cause the deadliest pandemic in a century emerged and began efficiently spreading in a manner that would soon engulf the entire planet. As a novel agent, there were no known medical countermeasures and the number of severe and fatal cases was rapidly increasing. Almost overnight, the global scientific community recognized the emergence of the significance of SARS-CoV-2 and shifted much of the entire biomedical complex towards combating the virus. By mid-January 2020, the virus’ genome had been fully sequenced and published; in February, the first clinical trials of therapeutic medical countermeasures began in the USA and by the beginning of March, the first vaccine candidate entered a phase I trial, a mere 42 days following the sequencing of the virus.^1,2 This was an unprecedented pace of research made possible by foundational research performed for decades (and continues to the present), with new medical countermeasures and newer clinical trial approaches that will have a lasting impact for future events. This brief report aims to summarize the development and progression of medical countermeasures against SARS-CoV-2 by highlighting important trials, select preventatives and therapeutics, and describe prospects for preparedness.

Absence of therapeutics in the initial stages of the pandemic

During the initial stages of the pandemic, severe disease and high sheer numbers of patients contributed to immense strain on hospitals, with up to 20% of symptomatic individuals who presented for medical care progressing to severe or critical disease with pneumonia, acute respiratory distress syndrome, multisystem organ failure, hypercoagulability and dysregulated immune responses that carried a very high mortality.³ Initial treatments included measures similar for acute respiratory distress syndrome in the pre-pandemic era, including early intubation and invasive mechanical ventilation, prone positioning and aggressive diuresis. Extracorporeal membrane oxygenation was initially used as a salvage therapy, and non-invasive mechanical ventilation was avoided over fears of aerosol generation. As a result, hospitals and intensive care units became rapidly overwhelmed.

Thus, from the outset, medical countermeasure development was focused on those with severe disease and examined steroid usage and the repurposing of older medications. In addition, the need for rapid dissemination of quality data to clinicians in the field was greater than the ability of traditional clinical trials to deliver. Just several months into the global declaration of a public health emergency of international concern by the World Health Organization (WHO), more than 1000 interventional trials were registered, many platform in nature.⁴ A platform trial is a randomized, adaptive methodology originally borrowed from the field of oncology that makes it possible to assess several interventions simultaneously through multiple arms under a pre-established set of rules and infrastructure. The adaptive design allows for continual review and modifications after initiation such as the addition or cessation of treatment arms as data becomes available, in comparison to a common control group, without undermining validity. This novel approach allows for flexibility in adding/dropping arms from the trial in real-time and provides the ability to release results in a rolling manner.^5,6 One of the most well-known adaptive platform trials is the randomized embedded multifactorial adaptive platform in severe community-acquired pneumonia (REMAP-CAP), which had been running since 2016. REMAP-CAP was able to transition into a ‘pandemic mode’ to explore treatments for COVID-19 in February 2020. The model and its design provide for broad information release that is precise as well as allowing for the inclusion of new study arms tailored to specific pandemic aims, and has laid the foundation for more clinical trials and platforms to emerge.⁷

RECOVERY trial

The most well-known platform in the UK is the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which launched in March 2020. The speed of effective data gathering and release of conclusive results (which first occurred on 3 June 2020) have been impressive.⁸ The trial first enrolled patients within 2 weeks of protocol submission, and has since expanded to Indonesia, Nepal and Vietnam. RECOVERY is a multi-arm adaptive clinical trial with new treatments added as it progresses, and other arms closed as results are examined. Such a design minimizes administrative loads to hospital staff as clinical attention can be focused on care for patients.^4–6,8

Four months into the pandemic, close to 100 clinical trials worldwide were investigating the efficacy of hydroxychloroquine for COVID-19. By June, after studying the treatment in more than 4000 participants, the RECOVERY team announced that the treatment was ineffective, and in the subsequent publication that followed in November in the New England Journal of Medicine (NEJM), they specified that those who received the treatment did not have a lower incidence of death at 28 days than those who received the standard of care at the time.⁸ Another notable finding by RECOVERY was the benefit of dexamethasone in patients hospitalized with COVID-19 (those with severe disease). This controlled, open-label arm enrolled more than 6400 patients requiring supplemental oxygen or mechanical ventilatory support with the endpoint of all-cause mortality within 28 days. Mortality was significantly lower in those who had received dexamethasone (22.9%) versus the control group (25.7%) but not among those who had not been receiving oxygen support.⁹ At the time, no therapeutic had yet been shown to reduce mortality in patients with more severe COVID-19. These preliminary results were also published in NEJM on 17 July 2020 and had immediate impact on acute care approaches worldwide. RECOVERY has thus far tested 10 interventions: eight repurposed therapeutics, one newly developed and convalescent plasma (CP).¹⁰

PRINCIPLE trial

As health care systems became overwhelmed with patients it became apparent that preventing hospitalizations was going to be crucial to preventing the collapse of the global system. For that goal, the need to develop effective outpatient therapies—especially for those who were at risk of serious illness and therefore hospitalization—was paramount. Into this arena, the Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE), led by the University of Oxford and funded by UK Research and Innovation and the National Institute for Health Research was launched in March 2020 to test multiple therapeutic candidates rapidly and efficiently at a population level. This adaptive platform evaluated five potential therapeutics, two of which are still under study.¹¹

PRINCIPLE initially showed that in the absence of other indications, the macrolide antibiotic azithromycin and the tetracycline antibiotic doxycycline did not benefit COVID-19 patients but merely put them at increased risk of side effects from the drugs as well as increasing the risk for antimicrobial resistance in the community: a longer term threat.¹² Of note, the trial has also found that colchicine does not improve outcomes for COVID-19 patients with mild to moderate disease, and in April 2021 announced that the inhaled steroid budesonide reduced the time to self-reported recovery by 3 days in adult patients over the age of 65 or over the age of 50 with comorbidities, but not hospitalization.¹¹ Both the RECOVERY and PRINCIPLE trials demonstrated that when time-critical results and guidance are needed, adaptive platform designs are effective approaches to meet that need during large-scale disasters.

Initial antivirals and monoclonals

On the basis of the evolving understanding of the pathogenesis of COVID-19, two different targeting processes have been identified. Early on, the disease is driven by direct cellular destruction and replication of the SARS-CoV-2 virus and later in the course, the disease is driven by a dysregulated immune/inflammatory response.³ Direct antiviral therapies have thus been found to be most efficacious early in the course of disease while immunosuppressants are likely more effective after progression. Several antiviral therapeutics have been identified along with additional interventions and monoclonal antibodies. The first is remdesivir, a ribonucleotide analogue inhibitor of viral RNA polymerase originally developed to treat RNA viruses with pandemic potential such as the Coronaviridae family of viruses (including SARS-CoV-1 and MERS-CoV). It was subsequently investigated for Ebola virus disease and Marburg virus before studied as a medical countermeasure against COVID-19.¹³

In vitro, it has shown significant broad antiviral activity and, in October 2020, the ACTT-1 trial was published, a double-blind randomized placebo-controlled trial of remdesivir among hospitalized patients with evidence of lower respiratory tract infection for 10 days with a primary outcome time to recovery. A total of 1062 patients underwent randomization and the trial showed those who received remdesivir had a median recovery time of 10 days versus 15 days among those who received placebo. Furthermore, estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 1%, and 11.4% with remdesivir and 15.2% with placebo by day 29. Thus far, the aggregated data on remdesivir show a faster time to recovery in patients who received remdesivir but no clear evidence of a survival benefit.¹⁴ It is currently recommended to treat patients who are hospitalized and at risk for severe disease, and the results of several studies showed the use of remdesivir plus dexamethasone improved clinical outcomes.¹⁵

Among other antivirals for those who have mild to moderate disease but with risk for progression to severe disease, are ritonavir-boosted nirmatrelvir (marketed as Paxlovid) and molnupiravir (Lagevrio). The former is an oral protease inhibitor with demonstrated activity against all human coronaviruses.^16,17 This drug appears to reduce progression to severe disease for patients with high-risk conditions early in their course of infection and was initially trialled in non-hospitalized unvaccinated adults with mild to moderate disease.¹⁷ But, when trialled in unvaccinated people at low risk of progression to severe disease or in vaccinated people at high risk of progression to severe disease, it was found it did not reduce the duration of symptoms and did not have a statistically significant effect on the risk of hospitalization or death (although overall event rates were very low).¹⁸ Observational studies described low numbers of viral rebound and symptom recurrence, but such concerns are not a reason to avoid using the drug.^19,20

Molnupiravir is an oral prodrug of a ribonucleoside with antiviral activity against SARS-CoV-2, resulting in catastrophic viral mutations. Like Paxlovid it was given an emergency use authorization (EUA) in the USA for treatment of adults with mild to moderate disease with high risk of progression to severe disease. Initial large-scale trials enrolled high-risk, unvaccinated, non-hospitalized adults and reported molnupiravir reduced rates of hospitalization or death among these patients before the Omicron variant emergence.²¹ The drug appears to be less efficacious than Paxlovid and is currently recommended to be used when other options are not available.

Monoclonal antibodies have also been investigated for their potential in prevention and treatment of COVID-19. Monoclonal antibody immunotherapy is a form of passive immunity that has been approved and used to treat diseases such as asthma, autoimmune diseases and cancer for almost 40 years, and is particularly suitable for use in prevention and treatment of infectious diseases such as COVID-19. Unlike most antibodies produced by the body naturally, which are derived from multiple B-lymphocyte lineages, monoclonal antibodies are produced by a single B-lymphocyte clone with significant specificity for a target antigen, in this case the viral spike protein of SARS-CoV-2, preventing viral entry into cells. By doing so, the monoclonal antibodies induce direct cell toxicity, immune-mediated toxicity, vascular disruption and effective immune modulation, thereby hopefully reducing progression to severe diseases, hospitalization and death.²² Thus far, four monoclonal antibody treatments have received EUAs in the USA for the treatment of outpatients with mild to moderate COVID-19: balmlanivimab, bamlanivimab plus etesevimab, casirivimab plus imdevimab, sotrovimab and bebtelovimab. However, they are no longer authorized for use as they were developed prior to the Omicron variant and subvariant emergence, and those variants demonstrate significant resistance. An additional monoclonal antibody formulation of tixagevimab plus cilgavimab (Evusheld) was authorized for pre-exposure prophylaxis in high-risk immunosuppressed individuals, but again many Omicron subvariants are expected to be less susceptible to the drug and in many places (including the USA) is no longer authorized for use.²³

Last, CP therapy has been investigated as a potential medical countermeasure with every emerging viral pathogen for the purposes of conveying passive immunity through plasma from donors who have recovered from disease regardless of vaccination status. In 2020, the USA Food and Drug Administration (FDA) issued an EUA for hospitalized patients but has since been revised to only include those inpatients or outpatients with COVID-19 who are immunosuppressed or receiving immunosuppressing treatments. Evidence to support its use has been limited; no randomized, adequately powered trials evaluating the approach have been published; some subgroup analyses of low-quality studies have suggested benefit and but are large amounts of heterogeneity. It is important to note that testing for high-titre CP measures antibody levels, not the neutralizing activity nor does it account for subvariants. Currently, the US National Institutes of Health COVID-19 Treatment Guidelines makes note that there is insufficient evidence to recommend either for or against the use of CP in immunocompromised patients, although some members of the guidance committee suggest its consideration in immunocompromised patients if a person is infected with a similar variant to that of a vaccinated donor. The Guidelines Committee recommends against the use of CP in immunocompetent patients who are hospitalized and has determined there is not enough evidence for CP usage in non-hospitalized patients. The WHO recommends against CP administration in patients with non-severe disease while advocating for usage only as a part of a clinical trial in those with severe illness. Thus, CP remains a controversial intervention, although some advocate its use, especially with no monoclonal antibody products currently authorized.^24,25

Immunomodulatory therapy

In patients with COVID-19, an immune-related inflammatory response has also become increasingly understood both within and without the pulmonary system. Patients can develop hyperinflammation partially driven by transcription factors (such as NF-kB) leading to increased tumour necrosis factor and interleukin-6 (IL-6) production, especially in bronchial epithelial cells.²⁶ IL-6 is a known proinflammatory cytokine produced by a variety of cell types, and infection from SARS-CoV-2 has been linked to elevated levels in the blood stream. Both the RECOVERY and REMAP-CAP trials evaluated the use of tocilizumab (an anti-IL-6 monoclonal antibody typically used for autoimmune diseases and cytokine release syndrome) in combination with standard-of-care corticosteroids and found statistically significant survival benefit, especially in patients with rapid respiratory decompensation in the setting of extreme inflammation as measured by elevated blood C-reactive protein levels. By contrast, two other large randomized controlled trials found that tocilizumab did not reduce all-cause mortality. Nevertheless, in December 2022 the FDA approved the use of tocilizumab for COVID-19 in hospitalized patients receiving systemic corticosteroids and who require at least supplemental oxygen.²⁷

Additionally, Janus kinase (JAK) inhibitors such as baricitinib and tofacitinib have been targeted as an important immunomodulatory therapy. JAK inhibitors interfere with phosphorylation of signal transducers and transcription proteins involved in vital cellular functions, signalling, growth and survival. Baricitinib, an oral JAK inhibitor that has exhibited dose-dependent inhibition of IL-6 induced phosphorylation may also have direct antiviral effects by blocking SARS-CoV-2 entry into cells. In the RECOVERY trial, baricitinib was associated with a survival benefit in hospitalized patients, with a treatment effect most pronounced among patients receiving high-flow supplemental oxygen. Currently, baricitinib is indicated for hospitalized patients who require oxygen therapy (conventional flow, high-flow devices, non-invasive ventilation or mechanical ventilation) and tofacitinib when the former is not available. And, in general, when patients already receiving corticosteroids and have rapidly increasing oxygen needs with evidence of systemic inflammation, either an IL-6 inhibitor or a JAK inhibitor is indicated.²⁸

Ineffective medical countermeasures

Many high-profile treatments have been shown to not only not improve outcomes ,but to also be very harmful to those with COVID-19 with many of these results coming from the adaptive clinical trials and others through traditional trial designs. Among home-remedy treatments that have been found ineffective are various types of teas, essential oils, herbal therapies (such as oleander/oleandrin), colloidal silver products, CBD-infused supplements and Vitamin C.

Two of the most high-profile therapies, hydroxychloroquine and ivermectin, have also been shown to not be beneficial in rigorous trials. Aside from the RECOVERY trial, another randomized trial investigating the potential use of hydroxychloroquine (an anti-malarial medication) was completed in the USA and Canada in 2020 and showed the drug failed as post-exposure prophylaxis.²⁹ A third, persuasive trial was completed in July 2020 in Brazil. That trial included 504 patients with mild to moderate COVID-19 in 55 hospitals and looked at the use of the drug either alone or in combination with azithromycin in reducing severity of illness or cure. It found it did not improve clinical status at 15 days compared with standard of care and contributed to greater cardiac and hepatic adverse events.³⁰ Around the same time, the FDA revoked the original EUA and prohibited the prescribing of the drug for off-label indications.³¹

Also in June 2020, a brief report appeared in the journal Antiviral Research that reported anti-SARS-CoV-2 activity of the anti-parasitic drug ivermectin in vitro but at doses much higher than those approved for humans. Ivermectin is an FDA-approved agent against parasites, but in vitro has demonstrated broad antiviral activity. Because it is also available in a veterinary format that does not require a prescription (and is also cheap), it became attractive despite a lack of evidence in vivo.³² Doses significantly higher than tolerated or recommended for humans were consumed, misinformation spread rapidly and notifications to poison control centres increased from adverse events. In February 2022, the I-TECH randomized controlled trial was published, attempting to determine the efficacy of ivermectin in preventing progression to severe disease among high-risk patients, conducted at 20 public hospitals in Malaysia. The drug plus standard of care or standard care alone was tested for 5 days with symptomatic monitoring and laboratory testing with a primary outcome being the proportion of patients who progressed to severe disease with hypoxia. The trial enrolled 490 patients and ultimately more patients in the ivermectin group progressed to severe disease: ivermectin did not prevent progression.³³

Then, ultimately, several large-scale randomized controlled trials were completed: the TOGETHER trial, published on 5 May 2022, was a double-blind, randomized, placebo-controlled adaptive platform trial with symptomatic SARS-CoV-2 positive patients in Brazil with at least one risk factor for severe progression of disease. The participants were randomized to receive ivermectin daily for 3 days or a placebo with compositive outcomes of hospitalization due to COVID-19 within 28 days or visit to an emergency department due to clinical worsening within the same time frame. The study concluded that treatment with ivermectin did not result in a lower incidence of medical admission or emergency department observations.³⁴

Then in October 2022, yet another randomized clinical trial attempted to ascertain whether ivermectin, taken daily for 3 days, shortens symptom duration and/or hospitalization in outpatients in the USA with mild to moderate COVID-19. This trial was conducted during the Delta and Omicron variant predominance and included 1591 outpatients, finding that among those who were treated with ivermectin versus placebo the drug did not significantly improve time to recovery and noted more hospitalizations in the ivermectin group. Ivermectin did not decrease the severity of disease, nor the length of time patients experienced symptoms. No good-quality, large-scale trial has provided reliable evidence supporting the use of ivermectin to treat the virus.³⁵

Treatment guidance

Early in the pandemic, the US National Institutes of Health (NIH) COVID-19 Treatment Guidelines were developed to provide clinicians with guidance on caring for patients with the disease. As information about the optimal management of the disease has changed and evolved quickly, guidance has been updated frequently to adapt to an ever-changing landscape to reflect new data and information; the US approach is one example of several organizations worldwide, other examples being the National Institute for Health and Care Excellence (NICE) of the UK and the WHO Therapeutics and COVID-19: Living Guideline. The membership of the US panel includes representation from federal agencies, healthcare organizations, academic institutions, professional societies: the American Association of Critical-Care Nurses, the American Association for Respiratory Care, the American College of Chest Physicians, the American College of Emergency Physicians, the American College of Obstetricians and Gynecologists, the American Society of Hematology, the American Thoracic Society, the Biomedical Advanced Research and Development Authority, the Centers for Disease Control and Prevention, the Department of Defense, the Department of Veterans Affairs, the FDA, the Infectious Diseases Society of America, the NIH, the Pediatric Infectious Diseases Society, the Society of Critical-Care Medicine and the Society of Infectious Diseases Pharmacists.³⁶

The creation of such panels has been essential to ensuring the most accurate and high-quality data is compiled, analysed and disseminated to bedside clinicians in the form of rated recommendations. The panels have evaluated data, its source, the type of study, the quality and suitability of methods, number of participants and observed effect sizes. This has positioned the healthcare system for further protection against future pandemics and addresses a critical need: the delivery of good, evidence-based practice measures. Panels such as those in the US approach continue to review available data and assess scientific rigour and validity. And, of course, guidelines are recommendations based on evidence, not mandates. Table 1 summarizes the above medical countermeasures used for treatment and prevention of infection.

Table 1.

COVID-19 therapeutic medical countermeasures

Current recommended therapeutics for outpatients	Current recommended therapeutics for inpatients	Previously recommended therapeutics	Ineffective therapeutics
Paxlovid (nirmatrelevir/ritonavir)	Veklury (remdesivir)	Evusheld (tixagevimab/cilgavimab)	Hydroxycholorquine
Lagevrio (molnupiravir)	Corticosteroids (dexamethasone, methylprednisolone)	REGEN-COV (casirivimab/imdevimab)	Ivermectin
Veklury (remdesivir)	JAK inhibitors (barticitinib, tofacitinib)	Bebtelovimab	Fluvoxamine
CP	Interleukin-6 inhibitors (Sarilumab, tocilizumab)	Bamlanivimab ± estevimab
	CP	Sotrovimab

Source: HHS.gov; Covid19treatmentguidelines.nih.gov.

Vaccine development and rollout

The knowledge behind mRNA technology and vector vaccine technology is not new. In fact, in the case of mRNA delivery, the technology was based on research conducted at Harvard University in 1984, in which several colleagues used a synthesized RNA enzyme to make biologically active mRNA. With the addition of fat droplets, researchers tested mRNA as treatments in rats for influenza as well as cancer vaccines throughout the 1990s. In the 2000s, funding was difficult to obtain and the mechanisms were not developed on a large scale.³⁷ In 2020, the FDA gave EUA to two mRNA COVID-19 vaccines produced by Pfizer/BioNTech and Moderna, and the initial roll out was slated to healthcare workers and those with high-risk conditions to protect the stability of the capacity of the healthcare system and to protect those at greatest risk for severe disease.³⁸ These vaccines work by using modified mRNA to induce cells to produce the viral spike glycoprotein of SARS-CoV-2. This protein then triggers an immune response in the body to produce neutralizing antibodies against the virus.

In parallel, a viral vector vaccine was developed by Johnson & Johnson in conjunction with Janssen Pharmaceuticals. This vaccine uses a recombinant, replication-incompetent adenovirus vector that encodes a variant of the SARS-CoV-2 spike protein to allow the body to develop an immune response like the mRNA vaccines. Initially the Johnson & Johnson/Janssen vaccine required only one inoculation whereas the Pfizer/BioNTech and Moderna vaccines required multiple inoculations due to their prime/boost approach. In February 2021, the Johnson & Johnson/Janssen vaccine also received an EUA by the FDA. However, 2 months later, a pause in administration of the vaccine was enacted due to six reported cases of vaccine-associated thrombosis with thrombocytopenia syndrome (TTS), a rare but life-threatening clotting disorder in the setting of low platelets discovered in 1–2 weeks following vaccine administration. While the pause was lifted, on 5 May 2022 the FDA limited the use of this vaccine due to increasing reports of TTS, and on 1 June 2023 the FDA fully revoked the EUA, rendering the vaccine no longer recommended.³⁹ Another non-replicating viral vector vaccine known as Covishield (made by Oxford/AstraZeneca with the Serum Institute of India) uses another viral vector(a different chimpanzee adenovirus) and remains approved in 49 countries.

Both the mRNA and adenoviral ventures were made possible by Operation Warp Speed, a public–private partnership initiated by the US Government to facilitate and accelerate development, manufacturing and distribution of COVID-19 medical countermeasures.⁴⁰ The mass production of multiple vaccines and vaccine types allowed for faster distribution if clinical trials produced enough evidence and anticipated that some vaccines would not prove safe or effective. The goals were the following: support pharmaceutical companies in research of several vaccine candidates simultaneously; support vaccine manufactures in the rapid scaling of capacity; support simultaneous FDA review of Phase I-III clinical trials and coordinate with the Department of Defense for supply, production and deployment. Despite criticism of the distribution effort, poor coordination between federal and state governments, lack of funding and proper planning for mass vaccination campaigns, the multifaceted approach led to an exceptionally fast development approval timeline for EUAs.

A third major vaccine type that remains in use and recommended for COVID-19 is the Novavax Inc. COVID-19 Vaccine, Adjuvanted. This vaccine is a protein subunit vaccine, produced via a platform of insect cells and a baculovirus expression system, containing only the parts of the virus that best stimulate the human immune system.⁴¹ Novavax’s vaccine contains the SARS-CoV-2 spike protein as well as a matrix-M adjuvant; this adjuvant enhances the immune response. The vaccine, in a similar approach to the mRNA vaccine administration schedule, is also administered as a two-dose primary series. On 13 July 2022, the FDA granted an EUA for Novavax Inc.’s vaccine. Last, several inactivated SARS-CoV-2 vaccines have been approved in various countries, the most prominent being Sinovac’s CoronaVac whole virus vaccine, granted an emergency use listing by the WHO in May 2021. This was developed by the Chinese company Sinovac, and tested in Phase III clinical trials in Brazil, Chile, Indonesia, the Philippines and Turkey.⁴² While it has had mixed results against certain variants, CoronaVac does not need to be frozen throughout supply chains, a trait extremely beneficial to low and middle-income countries and contributing to it becoming the most administered COVID-19 vaccine worldwide.⁴³

Future directions

The Coalition for Epidemic Preparedness Innovations, founded in 2016 by the Bill and Melinda Gates Foundation and several national governments, finances independent research projects to develop vaccines against emerging and re-emerging infectious diseases. The Coalition for Epidemic Preparedness Innovations turned its attention to SARS-CoV-2 with the Agility project, encompassing five specific aims: (i) rapid identification of new variants of importance; (ii) rapid neutralization testing of medical countermeasures with those variants of concern; (iii) assessments in animal models of the pathogenesis of the variants; (iv) rapid reporting and dissemination on the activity of these variants and (v) the goal of achieving predictability and comparability across independent laboratory testing. This project was undertaken to align with the four stages of pandemic preparedness: (i) development of early warning systems and surveillance assets; (ii) a comprehensive alert system; (iii) rapid response capabilities and (iv) rapid deployment of medical countermeasures to mitigate downstream effects.⁴⁴ The current pandemic and innovative trial designs has made clear that flexibility and agility essential to achieving those goals.

In early December 2021, as COVID-19 continued to reach yet another surge, the largest randomized trial of therapeutics was launched. Known as the PANORAMIC trial, it has been built on all the adaptive platform strategies that have come before and is focused on vaccinated patients in outpatient settings who remain at highest risk of severe disease progression throughout the UK. Still ongoing, the first results of the efficacy of molnupiravir to reduce the frequency of COVID-19 hospitalizations and death was studied in 26 411 patients. Results were published in The Lancet 1 year later and added evidence that vaccination is the best means for preventing severe disease and death from COVID-19.⁴⁵ But such immense scale and rapidity of the trial once again demonstrates that adaptive trial designs have paved the way for new advances in pandemic preparedness and response. As the world is vastly in need of fresh thinking, we must be able to pivot, adapt and adjust our approaches based on the rapid delivery of quality evidence that contributes the most to patient-centred care.

Funding

Internal funding was utilized. This paper was published as part of a supplement financially supported by an educational grant from Roche Molecular Systems.

Relevant transparency declarations

A.A. has served as a consultant/speaker and has received honorarium from Pfizer and Merck.