Comparative Performance Evaluation of Personal Protective Measures and Antiviral Agents Against SARS-CoV-2 Variants: A Narrative Review

Remdesivir

Remdesivir is a monophosphoramidate prodrug of the nucleoside GS-441524. It was first approved on October 22, 2020, by Food and Drug Administration (FDA). ²⁹ Remdesivir is available as a single dose of 100 mg vial (5 mg/mL after reconstitution). Usually, the course of treatment takes 3 days. A single 200 mg loading dose for the first day and 100 mg were given once daily for the second and third days. ³⁰ It is used to prevent the RNA-dependent RNA polymerase of SARS-CoV-2. It was the first authorized antiviral for emergency use to treat Covid-19 in various countries. ¹⁰ Several variants of SARS-CoV-2 (Alpha, Beta, Gamma, Delta, and Omicron) are susceptible to remdesivir. ³¹ Both adult and pediatric mild to moderately ill Covid-19 patients can be treated with remdesivir to decrease the risk of getting severe infection and hospitalization or even death. ³²

PINETREE clinical trial found that remdesivir reduces the hospitalization or mortality rate by 87% associated with Covid-19. ³³ The findings of the WHO-sponsored solidarity studies played a vital role in the conditional recommendation for using remdesivir in severe Covid-19. It has shown a significant reduction (17.0%) in relative risk of dying or progressing to require ventilation in individuals using supplementary oxygen at baseline, in comparison to the standard for care (relative risk (RR): 0.83; 95%). Additionally, according to solidarity, remdesivir therapy had a significant reduction rate (13.0%) of mortality risk for patients admitted to the hospital on supplemental oxygen and without mechanical ventilation than standard care (RR: 0.87; 95%). According to the same study, Covid-19 patients with ventilation support do not get enough benefits from remdesivir therapy. Furthermore, in a post hoc subgroup analysis, remdesivir-treated patients who received lower flow oxygen at baseline had a decreased mortality compared to placebo (HR: 0.30; 95%). ³⁴

Nirmatrelvir and ritonavir combination

It is effective to combine nirmatrelvir and ritonavir in treating infections due to the Omicron variant. ³⁵ Emergency Use Authorization (EUA) of PAXLOVID is issued by the FDA on December 22, 2021, for the treatment of Covid-19. ³⁶ This combination is available in the market as a trading name of Paxlovid. Nirmatrelvir is a primary protease inhibitor of SARS-CoV-2. Ritonavir is a protease inhibitor of HIV-1 and an inhibitor of CYP3A. Ritonavir has not demonstrated any efficacy against SARS-CoV-2. However, it can stop nirmatrelvir from being metabolized by CYP3A, increasing its plasma concentrations to prevent SARS-CoV-2 replication. ³⁷ The medicines are combined and given twice daily for 5 days. Ritonavir 100 mg one tablet and nirmatrelvir 150 mg 2 tablets are administered together. ³⁸ Clinical data support that nirmatrivir-ritonavir decreases Covid-19 related hospitalization or mortality by 89.0% relative to placebo in individuals who have risk factors for disease development and are unvaccinated. ³⁹ According to a study, a 5-day therapy of nirmatrivir-ritonavir is effective and reduces hospitalization and mortality among pediatric Covid-19 patients. ⁴⁰ Geriatric Covid-19 patients are at higher risk of developing severe respiratory symptoms. Moreover, a 5-day course of Paxlovid helps to reduce the disease severity and hospitalization among the older population in China. ⁴¹ However, some side effects can be happened after taking Paxlovid including, allergic reactions, liver problems, resistance to HIV medicines, high blood pressure, etc. ³⁸ There is a chance of reducing nirmatrelvir or ritonavir plasma concentration if Paxlovid co-administer with potent CYP3A inducers. ⁷

Molnupiravir

Molnupiravir is another oral antiviral drug for treating Covid-19. ⁴² It helps to prevent the SARS-CoV-2 replication and gives activity against different variants (Alpha, Beta, Gamma, Delta, and Omicron) of SARS-COV-2.43 On November 4, 2021, molnupiravir received its initial approval for treating mild to moderate Covid-19 patients. ⁴² Usually, 800 mg is taken every 12 hours for 5 days. ⁴³ A study found that molnupiravir reduces the hospitalization or mortality rate by 50.0% associated with Covid-19. ⁴⁴ Patients from Shenzhen’s Third People’s Hospital participated in an experiment. This study shows that molnupiravir increases viral RNA clearance in Covid-19 patients due to the Omicron variant (Molnupiravir group: 76.3% against control group: 51.6%). ⁴⁵

Monoclonal antibody

Monoclonal antibodies have been considered for the treatment since the beginning phases of Covid-19. There are 4 types of monoclonal antibodies- bamlanivimab (DB15718) plus etesevimab (DB15897), casirivimab (DB15941) plus imdevimab (DB15940), sotrovimab (DB16355) and tixagevimab (DB16394) plus cilgavimab (DB16393). ⁴⁶ It is usually used to treat non-hospitalized individuals who are at high hospitalization risk. Casirivimab plus imdevimab or bamlanivimab plus etesevimab are recommended for non-Omicron VOCs. A longer duration of action is achieved by sotrovimab. It also has therapeutic activity against a wide range of VOCs. Because of the decreased susceptibility to omicron, the FDA postponed the use of bamlanivimab plus etesevimab and casirivimab plus imdevimab. ¹⁰

Oxford-AstraZeneca vaccine

Oxford University and AstraZeneca jointly developed the recombinant Covid-19 vaccine named ChAdOx1 nCoV-19 (AZD1222). AstraZeneca has granted a license to the Serum Institute of India (SII) to produce the SII-Covishield vaccine. Oxford-AstraZeneca used non-replicated Chimpanzee adenoviruses to develop their Covid-19 vaccine. ⁵⁰ To trigger an immune response, a protein is produced by the DNA vector that resembles the viral s-peptide. Following the introduction of the DNA into the cytoplasm, it enters the cell nucleus. It is turned into mRNA by the host enzymes rather than being incorporated into the cellular DNA and then tends to way back into the cytoplasm where it interacts with the ribosomes of the host cell to yield translated proteins. The stimulation of antibodies, B-cell, T-cells, and plasma cells are occurred at this phase due to similarities in the mechanisms of DNA and RNA vaccines. ⁵¹ To determine the vaccine effectiveness, a randomized controlled study was conducted that showed the Ox-ford-AstraZeneca Covid-19 vaccine efficacy was 70.4% against symptomatic Covid-19. ⁵² According to the clinical study results in Ontario, the effectiveness was 62.0% against the Beta strain (B.1.351) of AZD1222 vaccine ⩾14 days after administration of the first dose Same report showed that one dose of ChAdOx1 prevented 41% of symptomatic infections by Gamma variant, ⩾14 days after administration of the first dose. ⁵³ A test-negative case-control study was conducted in England that showed vaccine effectiveness was approximately 67% with 2 doses of the vaccine against the Delta variant. ⁵⁴ Another case-control study was conducted in England to assess the efficacy of the vaccine against symptomatic disease caused by the omicron variant. The effectiveness was 48.9% after the administration of the second dose of the vaccine. ⁵⁵

Janssen Ad26.COV2.S vaccine

The Janssen Ad.26.COV2.S is a recombinant adenoviral vector vaccine designed by Johnson & Johnson. After exposure to SARS-CoV-2, it generated potent responses of neutralizing antibodies and offered nearly complete protection. ⁵⁶ To trigger an immune response, a protein is produced by the DNA vector that resembles the viral S-peptide. Following the introduction of the DNA into the cytoplasm, it enters the cell nucleus. It is turned into mRNA by the host enzymes rather than being incorporated into the cellular DNA and then tends to move back into the cytoplasm where it interacts with the host cell ribosomes to yield translated proteins. The stimulation of antibodies, T-cells, B-cell, and plasma cells are occurred at this phase due to similarities in the mechanisms of DNA and RNA vaccines. ⁵¹ To estimate the vaccine effectiveness, a phase III clinical study was done to obtain the effectiveness among the people whose SARS-CoV-2 testing was negative. The vaccine efficacy of a single dose was 76.7% against severe critical Covid-19 at 14 days after administration. ⁵⁷ Another study showed the vaccine effectiveness related to hospital admission conducted in South Africa. The Effectiveness of that study was 62.0% and 67.0% against the Beta and Delta variants, respectively. ⁵⁸

Moderna-mRNA-1273 vaccine

It is an RNA-based vaccine designed by Moderna. A lipid nanoparticle is encapsulated to produce the mRNA-1273 vaccine. The mRNA-1273 Vaccine contains the full-length spike protein of the SARS-CoV-2 virus, which is prefusion stabilized and induces Covid-19. ⁵⁹ The SARS-CoV-2 spike glycoprotein is encoded by a nucleoside-modified mRNA in the vaccine, which is enclosed in lipid nanoparticles for more effective distribution inside the host cells. The vaccine aims to stimulate both T-cell and B-cell defenses against the spike protein. The vaccine uses a potent lipid nanoparticle delivery mechanism to prevent initial stimulation of interferon-associated genes are significant characteristics that boost its effectiveness. ⁶⁰ To assess the efficacy of the vaccine, a phase III clinical trial among the participants who were 18 years of age or older showed that the effectiveness against the Covid-19 disease was 94.1% after a double dose. ⁵⁹ A case-control study performed among adult participants of Kaiser Permanente Southern California (KPSC) that showed the efficacy of the vaccine was 98.4% against the Alpha variant within 2 weeks or more after the second dose. ⁶¹ An investigation from the Qatar population particularly working-age adults revealed that the vaccine offered 96.4% effectiveness against disease for the Beta strain. ⁶² The study demonstrated that the efficacy of the vaccine was 89.0% against the Gamma strain after administration of the first dose. ⁵³ The case-control study on adult KPSC participants reported that the vaccine efficacy was 86.7% against the Delta strain after the second dose. ⁶¹ In Canada, a retrospective cohort analysis showed that the Moderna vaccine was able to reduce infection and hospitalization rates by 92.0% and 97.0%, respectively. ⁶³ A report from Spain demonstrated that booster doses of Moderna vaccines were given among the participants aged ⩾40 years, and showed 52.5% effectiveness against the Omicron strain

Pfizer-BioNTech-Comirnaty vaccine

Pfizer-BioNTech has designed an RNA-based Covid-19 vaccine named Comirnaty. The Pfizer vaccine has similar mechanisms of action as Moderna. ⁶⁰ In Israel, a third dose vaccine of Pfizer-BioNTech was pushed into their citizens (age: 37-52 years) to evaluate the effectiveness. Both male and female participants were taken to conduct the study. The third dose was administered to the participants who had taken their second dose at least 5 months ago. It showed 91% effectiveness against symptomatic diseases of Covid-19. ⁶⁴ In Qatar, a retrospective cohort study conducted on their inhabitants reported that the vaccine effectiveness was 87.0% against the Alpha strain and 72.1% against the Beta strain. ⁶⁵ An observational analysis was conducted on symptomatic community-dwelling individuals in Canada which reported that this vaccine has 63.0% efficacy against Gamma strains. ⁵³ In the United Kingdom, an investigation was done in their populations (60 years of age or older) and demonstrated that the vaccine effectiveness was 90.0% against the Delta variant within 2 weeks or more after the second dose. ⁶⁶ Another investigation was performed in Canada in individuals (aged: 12-17 years) who reported that the vaccine effectiveness of the third dose was 62.0% against the symptomatic disease of the Omicron variant. ⁶⁷

Sinovac-CoronaVac vaccine

This Covid-19 vaccine is designed by Sinovac R&D Co., Ltd. Typically, this kind of vaccination is intramuscularly given and needs an adjuvant to stimulate an immune response that is targeted against various viral proteins. ¹ The SARS-CoV-2 virus is introduced into the African kidney cells (Vero-Cell) of the green monkey. It is mixed with aluminum hydroxide (adjunct) and inactivated using β-propiolactone. Antigen-presenting cells which are introduced into the body engulf inactive viruses. It incorporates antigenic markers that the immune system recognizes and responds to by producing antibodies. ⁶⁸ To estimate the vaccine effectiveness, a case-control investigation was done in adults aged ⩾70 years in Brazil that revealed the effectiveness of the 2 doses was 46.8% and 55.5% against symptomatic disease and hospitalization, respectively, because the Gamma variant within 2 weeks or more after the second dose. ⁶⁹ A retrospective cohort analysis from Colombia reported that this vaccine can reduce hospitalization and death rates by 67.2% and 77.1%, respectively, due to the Mu variant of coronavirus. ¹ During the outbreak of the Delta variant in May 2021 in China, an investigation performed among the participants aged 18 to 59 years showed 59.0% effectiveness for 2-dose vaccination against the Delta variant. ⁷⁰

Novavax NVX-CoV2373 vaccine

The Collaboration for the foundation of Epidemic Preparedness Innovations and American biotechnology Novavax combinedly designed NVX-CoV2373. The vaccine incorporates spike proteins into a nanoparticle (knuckle-shaped) which is injectable in combination with the patented Matrix-M adjuvant. The adjuvant is shown to have a well-tolerated and potent impact by promoting the passage of antigen-presenting cells through the site of injection and boosting immune response. ⁷¹ Following a post hoc study, 29 participants had the symptomatic disease (non-B.1.1.7 variant), while 66 participants had the Alpha variant. This investigational report of Phase III clinical trials reported that the vaccine gave 96.4% efficacy against symptomatic disease and 86.3% against the Alpha strain. In late 2020, investigations from South Africa indicated the appearance of B.1.351 (or beta variants), which had been linked to higher transmission, more severe infection, and varying degrees of immune resistance to Covid-19 vaccinations. This survey was conducted among the adult population and the effectiveness of the vaccine was found 51.0% against the Beta variant. ⁷²

Sinopharm BBIBP-CorV vaccine

Beijing Institute of Biological Products has designed Sinopharm, an inactivated BBIBP-CorV vaccine for treatment against Covid-19. ⁷ Once inactivated viruses get into the body, the immune system of the body stimulates the production of antibodies and make the body ready to respond against SARS-CoV-2. The SARS-CoV-2 dead copy in the form of a vaccine is administered intravenously. The immune system is then boosted using the dead antigens from the virus against further viral attacks. ⁷¹ There are many studies conducted to know the efficacy of this vaccine. An investigational phase III study was performed in UAE and Bahrain among adults (18 years). One of the 2 inactivated vaccines made from the SARS-CoV-2 HB02 and WIV04 strains, or aluminum hydroxide (alum) was given to each participant. Vaccine efficacy was found 78.1% for the HB02 group and 72.8% for the WIV04 group, compared with the alum group. ⁷³

Bharat Biotech BBV152/Covaxin vaccine

It is a Vero cell-based inactivated SARS-CoV-2 vaccine designed by Bharat Biotech. To enhance immune response and promote more durable immunity, the vaccine is used in conjunction with immune stimulants which are referred to as vaccine adjuvants (Alhy-droxiquim-II). The inactivated virus is combined with the Alhydroxiquim-II adjuvant from Kansas-based ViroVax to produce the vaccine candidate. ⁷¹ A study was performed in 25 Indian hospitals on randomized people who were aged ⩾18 years. This investigational Phase III study reported that the vaccine efficacy was 77.8% against symptomatic disease and 65.2% against the Delta strain. ⁷⁴ An investigational report demonstrated that the efficacy of the vaccine showed a 26-fold reduction against the Omicron variant, 6 months following the second dose. Contrary to Covishield vaccinated patients, those who received the BBV152 vaccine maintained anti-nucleocapsid antibodies for a long duration. ⁹ Among these vaccines, AstraZeneca, Janssen, Moderna, and Pfizer have shown better efficacy than others against Delta, Mu, and Omicron variants to prevent the pandemic situation. Vaccination should be widely promoted in several poor and developing nations to achieve the preventative goal.