Exploring the dual role of nirmatrelvir and bisphosphonates in COVID-19 treatment and immunity

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The unprecedented coronavirus disease 2019 (COVID-19) pandemic facilitated the rapid development and subsequent deployment of several novel and highly effective vaccines. However, the role of antiviral treatment remains important, especially for certain patient populations who are unable to mount an effective vaccine response or who are unwilling to vaccinate.

In a recent review published in the journal Dr Cellular and Molecular Immunology, researchers examined the therapeutic benefits of nimarelvir and its potential effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific adaptive immunity. Here, the researchers also discuss the immunomodulatory properties of bisphosphonates, a class of drugs traditionally used to treat bone disorders, and their potential role in mitigating severe SARS-CoV-2 infection.

Study: Interplay of drug therapeutics and immune responses to SARS-CoV-2. Image credit: peterschreiber. Media/Shutterstock

Nirmatrivir and adaptive immunity to SARS-CoV-2

Nirmarelvir is an orally available drug that inhibits the major proteinase (Mpro) of SARS-CoV-2. More specifically, nimatrelvir targets 3-chymotrypsin-like cysteine ​​protease (3CL).Pro), a protease that cleaves two polyproteins, pp1a and pp1ab, that are encoded by the SARS-CoV-2 ribonucleic acid (RNA) genome to exert its antiviral effect.

Paxlovide, a combination treatment of both nimarelvir and ritonavir, has been shown to reduce hospitalizations and deaths due to COVID-19 by up to 86%. Despite the reported efficacy of nimarelvir in the treatment of COVID-19, the extent to which this agent affects SARS-CoV-2-specific adaptive immunity remains unclear.

In murine models, nirmatrivir treatment reduced SARS-CoV-2-specific antibody and T-cell titers, thereby preventing severe infection. Secondary viral exposure further reduced the recruitment of memory B- and T-cells.

These results indicate that while nirmatrivir effectively prevents severe disease by reducing viral titers, it may affect the ability of the host immune system to recognize and fight SARS-CoV-2 in the future. Several mechanisms have been proposed to account for this effect. For example, by limiting the exposure of SARS-CoV-2 antigen(s) to the immune system, nirmarelvir compromises the mechanisms of naïve T- and B-cells.

Bisphosphonates and adaptive immunity against SARS-CoV-2

Prior to the development of the COVID-19 vaccine, the international scientific community attempted to repurpose existing drugs as potential therapeutics to treat this viral disease. Many existing drugs were evaluated for their potential to treat COVID-19 with both in silico And in vitro Analysis

Beyond their exceptional potential to inhibit osteoclast-mediated bone resorption, bisphosphonates may exert multifaceted immunomodulatory effects. Current indications for bisphonates include osteoporosis, Paget’s disease, and malignancy-induced hypercalcemia, as well as adjunctive treatment of certain breast cancers.

Bisphosphonates can be classified as amino-bisphosphonates or non-amino-bisphosphonates based on their nitrogenous and non-nitrogenous chemical composition, respectively. Amino-bisphosphonates are capable of modulating a variety of immune cells, including neutrophils, monocytes, γδT cells, and macrophages. Animal studies have shown that amino and non-amino bisphosphonates can enhance antibody and T-cell responses to viral antigens.

In an effort to better understand the potential clinical utility of bisphosphonates in the treatment of COVID-19, a previous study evaluated whether prior bisphosphonate treatment affected the outcome of COVID-19. Notably, people treated with amino-bisphosphonates had a three- to fivefold reduced risk of being diagnosed with COVID-19 or hospitalized for the condition.

However, additional studies are needed to fully evaluate the potential use of bisphosphonates as prophylactic agents in patients at risk for severe COVID-19.


A comprehensive evaluation of the long-term effects of all COVID-19 prevention and treatment interventions on antiviral immunity is crucial to understand the full spectrum of effects of these agents on the host immune response.

Many COVID-19 therapeutics have yielded promising results in randomized controlled trials, which have subsequently led to their approval for use in the treatment of SARS-CoV-2 infection. However, more comprehensive data may help establish definitive conclusions on their long-term effects.

Managing the spread of SARS-CoV-2 and preventing severe COVID-19 outcomes appears to depend on a delicate balance between immediate treatment and ensuring long-term immunity. Thus, the emphasis is on integrating all therapeutic solutions for COVID-19 with sound scientific findings.

Journal Reference:

  • Fumagalli, V., and Iannacone, M. (2023). Interplay of drug therapeutics and immune responses to SARS-CoV-2. Cell and Molecular Immunology. doi:10.1038/s41423-023-01098

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