Navigating the Evolving Landscape of COVID-19: Challenges and Opportunities in Vaccine and Therapeutic Development
- 1. Evidence Based Research Institute, San Diego, USA
- 2. Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, US
- 3. InCSD LLC, Kansas, USA
- 4. Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
Abstract
New therapeutics and vaccines have had a significant impact on the COVID-19 pandemic, with lower mortality and morbidity reported in which host immunity from either vaccination or previous infection may be playing a significant role. However, High-Risk and Immunocompromised Patients (HRIP) largely contribute to the current hospitalizations and infections cases and are still in need of new countermeasures. Treatment or prevention of COVID-19 clinical trials with healthy volunteers are now much more difficult due to lower attack rates. However, clinical trials in the HRIP population create an opportunity to develop new vaccines and therapeutics alternatives. We propose clinical trials in the HRIP population to improve outcomes and be better prepared for possible next waves of the COVID-19.
Keywords
• Antivirals
• COVID-19
• Clinical Trials
• SAR-Cov-2
• Immunocompromised
• Vaccine
CITATION
Moss RB, KottIlil S, Rojas LA, Wolfe CR. (2024) Navigating the Evolving Landscape of COVID-19: Challenges and Opportunities in Vaccine and Therapeutic Development. Clin Res Infect Dis 8(1): 1062.
INTRODUCTION
Since the beginning of the pandemic over 7 million people have died of CIVID-19 [1]. According to the Center for Disease Control and Prevention (CDC) recent update entitled “The Changing Threat of COVID-19”, hospitalizations and deaths are declining due to COVID-19, but community outbreaks continue sporadically [2]. For example, the CDC noted that hospitalizations have decreased by over 60% compared to their peak in 2021. Even more dramatic has been the decline in death attributable to COVID-19 of approximately 83% decrease since early in the pandemic. Based on the above information, the CDC is recommending isolation for only 5 days for healthy individuals who are low risk [3].
The COVID-19 landscape is changing with positive outcomes, due to several factors that may account for the lower hospitalization and mortality rates. Previous infection and vaccination with resulting immunity likely play a key role in these current outcomes. The CDC estimated by the second half of 2023, 98% of people 16 years or older have COVID-19 antibodies due to infection or vaccination compared to only 21% in January 2021[2]. In addition, cellular immunity with durable T cell responses is also likely induced by vaccination or previous infection. Therefore, both cellular and humoral immunity may be enhanced because of previous infection and vaccination resulting in better control of viral replication. The rapid development of vaccines and antivirals for COVID-19 is rightfully considered one of the success stories of the pandemic. It demonstrated the potential for the pharmaceutical industry and academia to respond to a public health emergency, and gain FDA emergency authorization, harnessing high rates of patient participation resulting in significant impact on disease morbidity and mortality. The risk benefit in public health has been significantly realized in the improved public health impact of COVID-19.
The most common endpoints in COVID-19 vaccines clinical trials were associated with protection of symptomatic disease and hospitalization [4]. The approvable FDA endpoints for oral antivirals treatment. were hospitalizations and death [5]. Successful public health measures that include vaccines and antivirals using the above endpoints have clearly had an impact on limiting hospitalizations and death due to COVID-19.
PERSPECTIVE
Better host immune control and available antivirals as well as changes in the virus itself may account for the current optimistic epidemiology of COVID-19. Because of these changes it is difficult to execute clinical trials in a healthy volunteer with immunity. However, a gap still exists for those patients that are high risk or immunocompromised. Although vaccines have been developed and are effective in healthy subjects, the treatment and prevention toolkit still have less or unknown efficacy in HRIP individuals, even in 2024. However, more treatment and vaccine development are needed. Of concern the constant mutation occurring in the S1 spike domains, current vaccines require regular updates and like influenza vaccine, we may not be able to predict the optimal viral epitopes for the circulating viruses at a given time. We also have observed clinical resistance to almost every monoclonal antibody and antiviral developed for COVID-19 [6].
There seems to be a sense that the US and the world is over with the worst of the pandemic, and there has been more complacency regarding public health COVID-19 with limited interest in developing new strategies in spite of the fact that COVID-19 still ranks as the 10th most common cause of death in the U.S.A for 2023. The change in urgency is exemplified by the National Institute of Health (NIH) clinical treatment guidelines being retired in August 2024. Public health retreat is now accompanied by significant difficulty in conducting clinical trials for the new treatment and prevention of COVID-19. Given the reduced severity of illness in the general population, the resulting death rates makes current FDA recommended endpoints in clinical trials more difficult, since to achieve clinical meaningful treatment effect requires much larger samples sizes. Other endpoints such as viral load are equally challenging in the low risk vaccinated population who rapidly reach undetectable without additional intervention [7]. The CDC has acknowledged that preexisting immunity has reduced the duration of viral shedding and spread of infection in the general population, making viral load a difficult endpoint in the otherwise healthy immunocompetent population.
In addition to treatment studies, pre- or post-exposure prophylaxis trials are also becoming difficult to execute. The secondary infection attack rates for SARS-CoV-2 are decreasing, compared to those previously observed, due to better control of virologic shedding. As a result, prophylaxis trials will now require substantially larger sample sizes compared to earlier in the pandemic, making them operationally and financially difficult to execute in a timely fashion. Finally, studies examining ‘Long COVID’ have become progressively harder, as the identification of at-risk and affected patients becomes challenging.
All the difficulties noted are inherent in clinical trials of healthy volunteers yet may not apply to high-risk populations such as the elderly or immunocompromised. These patients continue to bear the brunt of COVID-19-associated morbidity and mortality and remain the most in need of improved interventions. Indeed, immunocompromised patients are generally not able to develop high levels of protective serological immune responses to vaccines [8] and have higher rates of hospitalization compared to low-risk patients [9]. They are also not able to take current antivirals without concern for drug-drug interactions particularly with many immunosuppressants, such as tacrolimus [5]. Clinical trials of new therapeutics in these populations for both treatment and prevention can still utilize the viral load, and all other clinical outcomes suggested by the FDA [10].
CONCLUSION
The current decline in hospitalizations and deaths due to COVID-19 is a welcome development and should make us all cautiously optimistic. However, the virus continues to mutate and could someday be able to circumvent immunity even in healthy populations. Thus, there is an inherent need to develop new therapeutics and vaccines in the most at risk group and these are the appropriate populations for supporting clinical trials utilizing endpoints that can be achieved. Adaptive and innovative clinical trial designs in HRIP populations are strongly recommended as those designs provide a better opportunity to detect the effect signal, include early stopping efficacy, futility rules, increase the sample size, dropping or adding treatment arms, during interim analysis, etc., which is of great value for all stakeholders and patients. Such a targeted approach in these populations should allow for optimal preparedness for the next wave of the COVID-19 pandemic.