COVID -19 disease and why COVID treatments are important despite vaccination

COVID -19 disease and why COVID treatments

The world, today, is in the clutches of a global health crisis, which is upending lives. The impact is severe on people’s health, death rate, on societal norms and even economy. The origin of the pandemic can be traced back to December of 2019, from the city of Wuhan in China, where cases of severe pneumonia and respiratory distress was observed in a few workers associated with a seafood market. The disease was termed COVID-19 and the pathogen causing the disease was identified as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Most countries across the globe are reeling due to the pandemic and there has been no significant relief so far. The advent of vaccines and targeted treatment options is providing some respite, although the only fool-proof approach is stopping spread of new infections. Many countries have been in a state of constant or intermittent lockdown, restricting movement of public and trying to slow down spread. Despite vaccinations, the emphasis on masking, social distancing and personal hygiene has been reiterated by various public health organizations, around the world. 1, 2

 

Covid disease pathology

 

The need to discover or identify targeted treatment options and medications for COVID-19 is urgent and profound. The obvious line of defence is to inhibit viral replication using antivirals, but this may not be effective when the disease progresses to the inflammatory stages. The dilemma to choose between treatment options becomes a guessing game and leads to a time crunch for treatment to work. Understanding the pathology becomes key to finding effective treatment options.

 

COVID-19 histopathology picture shows pneumonitis, that encompass lung injury of the epithelial, vascular, and fibrotic patterns. Symptom onset timeline was formulated by analysis of these patterns in patients at different stages of disease. Epithelial changes, such as Diffuse Alveolar Damage (DAD) and denudation, were seen in all stages of disease. Vascular changes, like microvascular damage, fibrin deposits and thrombi, were seen in the early stages of symptomatic COVID-19 infection. This is particularly interesting as the vascular changes are exclusive to COVID-19 and hasn’t been observed in conventional ARDS and influenza. Contrastingly, fibrotic changes were observed only around 3 weeks after onset of symptoms. The SARS-CoV-2 virus was detected in other organs in addition to the lungs, including heart, liver, gastrointestinal tract, kidneys, skin and placenta. Pathological findings in other organs have been non-specific and warrants further research. However, some epithelial damage has been observed in other organs in later stages of disease progression, further evidenced by the presence of the virus in some urine and faeces samples. In some cases microvascular damage was seen in the heart, liver, kidneys, indicating systemic hyperinflammation. 3

 

 

Although we have come a long way in understanding the pathology, we still have plenty to learn in terms of the various stages and severity of COVID-19. Histopathological findings tend to vary and can even be modified by patients immunity, presence of co-morbidities, secondary infections and therapies such as steroids. Treatment for COVID-19 will have to be tailored based on new pathological evidence that may arise. 4

 

Treatment options

 

Clinical management plan for COVID-19, currently includes infections prevention, control measures and supportive care (oxygen supplementation, mechanical ventilatory support). The FDA approved drug remdesivir in one of the most popular choices for treatment in hospitalized patients over the age of 12 years 5. At the beginning of the pandemic therapeutic options were limited, creating an urgency in repurposing drugs and experimental therapies. A lot has been researched and today, COVID-19 management is better understood, leading to rapid development of vaccines and novel therapies 6.

 

The go-to treatment option that is predominantly used now is remdesivir, which is a broad-spectrum antiviral agent. Remdesivir is administered to hospitalized adults with mild-to-severe disease. A few other antivirals have been found to be useful in treatment of COVID-19. Specific interest has been on malarial drugs. Apart from antivirals, neutralizing antibody products and some immunomodulators have been considered. The table details some of the other treatment options that are in clinical use or have shown some success. This list is not exhaustive.

 

Table 1 Investigational and emergency use approved drugs/treatments for COVID-19 2, 6

 

  Drug/Treatment Primary indication Status for use in COVID-19
Antiviral      
  Lopinavir/ritonavir HIV Discontinued
  Ivermectin Anti-parasitic Clinical studies only
  Favipiravir Influenza Clinical studies only
Anti-SARS-CoV-2 Neutralizing Antibody products      
  Convalescent Plasma therapy Evaluated during SARS, MERS and Ebola Approved by FDA for severe life-threatening cases
Immunomodulatory Agents      
  Corticosteroids Lung inflammatory diseases WHO strongly recommends for use in critical cases
  Tocilizumab Rheumatological diseases Emergency use authorization for severe and critical hospitalized cases

 

Vaccines

 

The race to develop a vaccine for SARS-CoV-2 has been unprecedented and rapid. This is the first ever time that a vaccine has been developed and approved for emergency use, in the history of healthcare. Technology, better research and perseverance has led to first big breakthrough in managing the pandemic.

 

Pfizer BioNTech Vaccine: A mRNA vaccine developed by Pfizer and the German company BioNTech was the first to be approved for use and has shown 95% effectiveness in clinical studies. The vaccine delivers mRNA that code for the SARS-CoV-2 spike protein, against which the body mounts an immune response. This vaccine is administered in two doses, three weeks apart and needs to be stored at a temperature less than minus 94 degree Fahrenheit. 7

 

Moderna/NIAID vaccine: Another mRNA virus with similar mechanism of action as the Pfizer vaccine is the one developed by U.S Biotech company Moderna with National Institute of Allergy and Infectious diseases (NIAID). This vaccine is said to be around 94% effective, as observed in clinical studies and requires two doses given at an interval of four weeks. The advantage of Moderna vaccine over Pfizer is that it doesn’t need deep freeze storage and can be stored at minus 4 degree Fahrenheit. 7

 

Oxford Astrazeneca vaccine: Showing around 70% effectiveness is the vaccine developed by Oxford University and pharmaceutical firm AstraZeneca. The vaccine consists of weakened common cold adenovirus that naturally infects chimpanzees and has been modified to not replicate in humans. A gene that codes for the SARS-CoV-2 spike protein has been engineered into the adenovirus vector that leads to an immune response. 7

 

Johnson & Johnson – Janssen: Reporting a 72% effectiveness in studies, the Johnson and Johnson vaccine, Janssen is made up of a modified weakened common cold adenovirus, which cannot infect humans and codes for the SARS-CoV-2 spike protein. 7

 

Bharat Biotech vaccine: Covaxin is an inactivated coronavirus vaccine developed by Indian company Bharat Biotech with Indian Council of Medical Research and National Institute of Virology. Covaxin is administered in two doses, four weeks apart. 7

 

Sputnik V: Russian Gamaleya Research Institute developed a vaccine with two modified common cold adenovirus coding for the spike protein without replicating in humans. This vaccine was named Sputnik V. As per published Russian early data, the vaccine is said to be 91.4% effective. 7

 

Many more vaccines are still in development and in different phases of clinical studies. Considering the novelty of these vaccines, only time will tell how protective the vaccine elicited response really is and if and when a booster may be required. Another factor to look into is the ability of the SARS-CoV-2 to mutate and with discovery of new strains, the protective effects of the vaccine may or may not hold good. Population data will help answer a few of these questions. In research setting, phase 3 trials usually only look at the reduction of symptomatic COVID-19 cases and do not specifically look at reduction in severe disease or hospitalization. This is another aspect to further consider when our primary target is to reduce mortality. 8

 

We face tremendous uncertainty even with these vaccines, firstly due to a shortage of vaccine to adequately vaccinate a good percentage of the worlds population. Researchers are still unsure if the vaccines will protect against all strains or any new strains that may arise. One such situation arose with the identification of the Delta variant, first seen in India, with increases transmission and even re-infecting people who were already diagnosed with COVID-19 previously. Biotechnology and pharmaceutical companies have already started developing booster formulations, while the need for boosters is still under study. 9

 

Significance of treatments in the ever changing viral genome

 

Vaccinations programs are well underway in many countries, but the need for therapeutics for affected patients is still strong. So far, the only approved and well-known therapeutic is remdesivir. The European Union has already put together a strategy to address therapeutic research, development, authorization and manufacturing. A large number of new and repurposed drugs are being investigated as possible treatments for COVID-19. Nearly 4000 studies can be found on Clinical Trails.gov, that are constantly elucidating pre-clinical and clinical results for new experimental therapies. A list of all COVID-19 related clinical trials listed on WHO website can be found here. Let’s take a look at what is expected of a new or repurposed drug to be used as treatment for COVID-19. 10

 

Antiviral drugs:

 

An ideal antiviral drug candidate should meet the below criteria, in order to improve clinical outcome of COVID-19 patients: 10

  • Easily available with prescription or as over-the-counter access, which would help start the fight against the virus before it replicates in large number sin the lower respiratory tract.
  • Ease of administration and self-administered pill or nasal spray, not requiring the assistance of a healthcare worker.
  • Highly specific to SARS-CoV-2.
  • Safer and more effective that other standard care options.

 

Immunomodulator:

 

Cytokine and kinase inhibitors are the only type of immunomodulators studied so far, which block messengers that lead to out-of-control immune responses in severe COVID-19 cases. One major limitation is the knowledge gap in identifying and treating cytokine storms, as they can make stabilizing a patient’s health very difficult. Thus the need to identify other immunomodulating drugs is vital. 10

 

Cellular and gene therapies:

 

This is a relatively new concept and has a long way to go before it can be used as therapy for COVID-19. But proof-of-concept data from the Pfizer and Moderna vaccines have shown some promising avenues to explore in this front. Although, these are not gene therapies by themselves and only use mRNA to exploit the normal protein making process of the human cells, this has still opened doors to the possibility of using gene therapy as targeted treatment. 10

 

Neutralizing antibodies:

 

Neutralizing antibody therapies are more quickly achievable as compared to gene therapies, which still require a lot of research. Bamlanivimab is one therapy that has been approved by the FDA for emergency use in mild to moderate cases, who are at high risk for progressing to severe disease. As with antivirals, early treatment is more effective when using neutralizing antibodies. 10

 

Conclusions

 

The availability of safe and effective vaccines has been a big breather during the COVID-19 pandemic. Nevertheless, we will reach closer to the end of the pandemic only when we reach global herd immunity and stop the spread of the virus. We are nowhere near that, yet. Even after we have achieved herd immunity, vigilance is key, as the lookout for mutated variants needs to continue. A strong arsenal of treatment options will help us tackle any future outbreaks and mitigate some of the risks of mortality and hospitalization. Credit to scientists and researchers, that we know so much about COVID-19, it’s progression and treatment in such a short duration. Further research in the area of better and quicker treatment options for COVID-19 is paramount.

 

 

References:

 

  1. Everyone Included: Social Impact of COVID-19 | DISD. https://www.un.org/development/desa/dspd/everyone-included-covid-19.html. Accessed August 19, 2021.
  2. Ali MJ, Hanif M, Haider MA, et al. Treatment Options for COVID-19: A Review. Front Med. 2020;0:480. doi:10.3389/FMED.2020.00480
  3. Polak SB, Van Gool IC, Cohen D, von der Thüsen JH, van Paassen J. A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression. Mod Pathol 2020 3311. 2020;33(11):2128-2138. doi:10.1038/s41379-020-0603-3
  4. Shanmugam C, Mohammed AR, Ravuri S, Luthra V, Rajagopal N, Karre S. COVID-2019 – A comprehensive pathology insight. Pathol Res Pract. 2020;216(10):153222. doi:10.1016/J.PRP.2020.153222
  5. Therapeutic Options for COVID-19 Patients | CDC. https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html. Accessed August 19, 2021.
  6. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls Publishing; 2020. http://www.ncbi.nlm.nih.gov/pubmed/32150360. Accessed September 3, 2020.
  7. Quick guide: COVID-19 vaccines in use and how they work | Live Science. https://www.livescience.com/coronavirus-vaccines-authorized-for-use.html. Accessed August 19, 2021.
  8. Forni G, Mantovani A. COVID-19 vaccines: where we stand and challenges ahead. Cell Death Differ 2021 282. 2021;28(2):626-639. doi:10.1038/s41418-020-00720-9
  9. A Guide to Global COVID-19 Vaccine Efforts | Council on Foreign Relations. https://www.cfr.org/backgrounder/guide-global-covid-19-vaccine-efforts. Accessed August 19, 2021.
  10. Current and Future Therapeutic Options for COVID-19. https://www.nuventra.com/resources/blog/current-and-future-therapeutics-for-covid-19/. Accessed August 19, 2021.