Significance of Innate Immunity in Mitigating SARS-CoV-2 Infection

Friday, June 18, 2021

By: Subhash Dhawan - Retired Senior FDA Research & Regulatory Scientist

Continuously surging numbers of global COVID-19 cases caused by rapidly emerging SARS-CoV-2 mutants forming more contagious and deadly viral strains force our scientific capacity to find creative ways to control the pandemic. While current SARS-CoV-2 vaccines are quite effective in reducing the severity of the disease, hospitalization and deaths, none is yet known to provide complete protection from acquiring SARS-CoV-2 infections and to prevent reinfections of the recovered adults or possibly even the vaccinated population. It is time for us now to also focus on alternative approaches, such as evaluating the potential of the cellular innate immunity, the first-line of host defense mechanism against all invading pathogens, to retard the spread of SARS-CoV-2 infections, in addition to ongoing efforts on developing new variant-specific vaccines. As an attempt to prevent the COVID-19 pandemic from being completely out of control, this brief opinion reemphasizes the prospects of the innate immunity, a highly crucial component of the immune system, for evaluating its potential to mitigate SARS-CoV-2 infections.

The highly contagious novel respiratory coronavirus, SARS-CoV-2, is readily transmissible to one another in close proximity.1 The alarming number of COVID-19 cases continue to threaten human health and has greatly impacted us socially and economically. According to the May 16, 2021 WHO Coronavirus (COVID-19) Dashboard, there are 162 million COVID-19 global cases, including 3.3 million deaths, with 32.5 million COVID-19 cases and in excess of 579,000 deaths in the United States officially confirmed. These numbers are increasing on a daily basis. Traveling across the country and around the world is of immense global public health concern for the spread of this deadly disease. The seriousness of travel-related spread of SARS-CoV-2 variants is widely recognized; yet, realistically, it is beyond strict enforcement of regulatory control to prohibit individuals from traveling. This is neither practically possible nor is it a permanent solution to the problem.

Current medical options to treat SARS-CoV-2-infected individuals are limited, and full prevention of infections by effective vaccines to irradicate COVID-19 may be possible in the future; but, it has yet to be accomplished. Among a number of enormously growing general concerns are: (a) rapid increase of SARS-CoV-2 variants with reduced capacity of neutralization by the antibodies,2 in addition to their increased transmissibility and pathogenicity;3-6 and (b) global surge of COVID-19-positive cases, hospitalizations, and deaths. These serious issues constitute the highest priority for the safety of the public health, and are being taken into account for the development of safe and effective vaccines.

While immunization against individual pathogens has long been known to provide protection against infections and to reduce the severity of the disease, constantly emerging SARS-CoV-2 mutants and variant strains will continue to pose difficult challenges for the development of effective vaccines. Mutational changes in the viral genome are also problematic for specific and sensitive molecular in vitro diagnostic tests to detect SARS-CoV-2 infections. The concerns related to these moving targets are valid and warrant: (a) frequent genetic sequencing of the emerging variants to design fitting molecular and antigen tests for accurate diagnosis of SARS-CoV-2 infections; and (b) evaluating the potential of innate immune response in SARS-CoV-2 infections to reduce the rate of infections, in addition to the continued vaccination program.

The fundamental concept of innate immunity is based on the fact that it acts instantly to resist all invading pathogens. This non-specific protective mechanism provides initial protection against “invading pathogens”, regardless of strains, variants, and mutants, and precedes the secondary adaptive immune responses that are generated days or weeks after exposure to specific “invaded pathogens”. Therefore, logically and scientifically, the activation of innate immunity for enhancing its capacity to resist initial viral infections in conjunction with vaccination to subsequently produce antibodies could potentially yield a beneficial outcome for managing the COVID-19 pandemic. 

Activation of the innate immunity in attenuating SARS-CoV-2 infections has also been extensively discussed7 and reported by numerous investigators.8-12 Interestingly, in a recent report, Chumakov et al. suggest the stimulation of innate immunity by live attenuated vaccines, particularly oral poliovirus vaccine, as a temporary protective measure against SARS-CoV-2.13 While the mechanisms for general host defense response induced by unrelated previously approved vaccines remain to be elucidated for SARS-CoV-2, the authors present this strategy as a temporary yet potentially safe alternative option. Nonetheless, collectively, the knowledge gained in recent years on activated innate immunity signifies the stipulation of its capacity for cellular protection against SARS-CoV-2 infections.

The fact that initial cellular resistance to viruses and other pathogens by innate immunity diminishes their rapid replication to a certain extent, also provides sufficient time to generate the secondary immune responses while maintaining a low viral load. This is highly significant for retarding the disease progression naturally. However, despite immense capacity of the innate immunity to initially resist to the invading pathogens, it is swiftly overwhelmed by most viral infections. The weakening of the natural defense system to adequately protect the host,14-16 especially with limited medical options to effectively treat post-infections and related complications, pose extremely difficult medical challenges. In such circumstances, modulation of the innate cellular protective response directly17 or indirectly13,16 to restore its normal function may pave the ways for effective alternative or concurrent therapeutic strategies to reduce the newly emerged novel SARS-CoV-2 infections.18,19

A calculated regulation of the innate immunity to boost initial cellular resistance to viral infections could also enable the generation of subsequent effective secondary or adaptive humoral immune responses in the infected individuals to retard the disease progression. This general strategy can be complementary to the existing medical modalities for treating SARS-CoV-2 infections by applying new scientific tools to achieve a meaningful clinical outcome (i.e., providing additional concurrent preventive or therapeutic options to effectively control the COVID-19 pandemic), especially with the narrow pathogen- specificity of the vaccines developed against particular viral strains. A careful evaluation of the cellular host defense system is pivotal to broaden the scope of current medical options for mitigating SARS-CoV-2 infections by constantly emerging new viral variants.

By virtue of the innate immunity as a generic initial host protection mechanism to resist all invading pathogens, a sustained robust cellular immunity, along with vaccinations to generate secondary (or adaptive) immune responses, holds a potentially promising systemic approach for resolving SARS-CoV-2 infections and also for other future viral outbreaks, including influenza.

References

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  2. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7;2021. bioRxiv. https://doi.org/10.1101/2021.01.25.428137
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  6. Davies NG, Abbott S, Barnard RC, et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science 2021;372(6538):eabg3055. https://doi.org/10.1126/ science.abg3055
  7. International Symposium on Innate Immunity and COVID-19, Washington University School of Medicine, December 11, 2020.
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  11. Dogra P, Ruiz-Ramírez J, Sinha K, et al. Innate immunity plays a key role in controlling viral load in COVID-19: Mechanistic insights from a whole-body infection dynamics model. ACS Pharmacol Trans Sci. 2021;4(1):248-265. https://doi.org/10.1021/acsptsci.0c00183
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  18. Dhawan S. Innate cellular immunity for suppressing viral infections. Curr Trends Immunol. 2021;22:19-21. http://researchtrends.net/tia/article_pdf. asp?in=0&vn=22&tid=36&aid=6762
  19. Dhawan S. Necessity for the evaluation of stimulated cellular immunity against SARS-CoV-2 infection. Curr Trends Immunol. 2021;22 (Article in press)

About the Author

Dr. Subhash Dhawan is a viral immunologist. He retired after serving for nearly 25 years as Chief of Viral Immunology Section in the Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. Dr. Dhawan is now an independent writer and provides guidance on research and regulatory projects related to in vitro diagnostics, vaccines, and therapeutics. 

Contact: [email protected] - (202) 731-9886

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