On December 20, 2021, the EMA authorized a new NVX-CoV2373 vaccine with a different mode of action from the Pfizer and Moderna mRNA vaccines. The NVX-CoV2373 vaccine is a recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins. The NVXCoV2373 (Novavax) vaccine consists of 5 μg of a recombinant nanoparticle spike protein plus 50 μg of Matrix-M adjuvant. Early clinical data have demonstrated that a two-dose regimen administered at 3-week time intervals induces a robust immune response in healthy adult participants (Polack et al. 2020; Voysey et al. 2021). A phase 3, randomized, blinded, placebo-controlled study was performed to evaluate the efficacy, immunogenicity, and safety of NVX-CoV2373 in the prevention of COVID-19 in participants aged 18–84 years in the UK. A total of 15,187 participants were recruited. Data showed 86.3% efficacy against the B.1.1.7 (or alpha) variant and 96.4% efficacy against non-B.1.1.7 variants (Heath et al. 2021). Reactogenicity was generally mild, and the incidence of serious adverse events was similar in the Novavax group and placebo groups. Efficacy against the Omicron variant was not considered. Certainly, the new recombinant protein vaccine NVXCoV2373 (Novavax) represents a new weapon of prophylaxis against SARS-CoV-2.
The main therapeutic agents for the treatment of SARS-CoV-2 infection are immunomodulators/anti-inflammatory agents, anticoagulants, antivirals, and monoclonal antibodies. Recently, new oral antiviral agents such as molnupiravir and paxlovid have been approved and represent important therapeutic alternatives to remdesivir. Molnupiravir is an isopropyl derivative of the ribonucleoside analogue β-d-N4-hydroxycytidine (NHC); it is a prodrug that is immediately activated in its active form by plasma esterases. The active form of the drug then undergoes intracellular phosphorylation by host cell kinases to form an alternative substrate for viral RNA polymerase (Agostini et al. 2019). In vitro and in vivo tests show that molnupiravir was found to be a potent inhibitor of SARS-CoV-2 replication, (Fig. 1) (Zhao et al. 2021; Sheahan et al. 2021).
In addition, molnupiravir in phase I/II/III clinical trials demonstrated good efficacy and safety. Data indicate that molnupiravir reduced the risk of hospitalization or death by approximately 50% in non-hospitalized adults who had mild to moderate COVID-19 and were at risk for a serious disease outcome (Merck and Ridgeback’s 2021). In addition, molnupiravir has been shown to reduce the risk of hospitalization or death in all subgroups, with efficacy unaffected by the timing of symptom onset, underlying risk factors, or the type of SARS-CoV-2 variant (Gamma, Delta, and Mu). Another positive aspect is that the data demonstrate a generally good safety profile. The clinical trial showed that the incidence of any adverse event was comparable in the molnupiravir and placebo groups (35% and 40%, respectively), and the incidence of drug-related adverse events was also comparable (12% and 11%, respectively). In addition, fewer subjects discontinued study therapy because of an adverse event in the molnupiravir group compared with the placebo group (1.3% vs 3.4%) (Vitiello et al. 2021). Results from a clinical trial showed that 35.4% and 43.8% of individuals reported adverse events after administration of molnupiravir and placebo, respectively. No serious adverse events appeared, and the most commonly occurring non-serious adverse event was headache Molnupiravir (12.5%) and placebo (18.8%) (Painter et al. 2021). On March 23, 2022, molnupiravir received EUA from the Food and Drug Administration (FDA) (https://www.fda.gov/media/155053/downloadn.d.): the 800-mg daily dose for 5 days has been approved under EUA status as treatment for patients affected by COVID-19 and having mild-to-moderate symptoms. In another clinical trial, no serious adverse events were reported in all the patients who received 300- and 600-mg molnupiravir. The most common symptoms were loss of smell or taste, diarrhea, nausea, and cough (Khoo et al. 2021). The results of these trials revealed a well-tolerated safety profile of molnupiravir. To date, on ClinicalTrials.gov, there are 4 ongoing clinical trials evaluating the safety and efficacy of molnupiravir in patients with COVID-19 (Table 1). The results of the ongoing trial may further bring more clarity, especially on the efficacy of Molnupiravir in the new variant Omicron.
The new oral antiviral agent paxlovid is a combination of two active ingredients. The first, nirmatrelvir (PF-07321332), acts by inhibiting SARS-CoV-2 viral replication by blocking the SARS-CoV-2-3CL protease; the second is ritonavir, an antiretroviral indicated for the treatment of HIV, which is also an inhibitor of cytochrome P4503A and CYP2D6 used to slow the metabolism of nirmatrelvir. The antiviral drug must be administered within 5 days of the onset of symptoms to stop the development of serious disease caused by the infection. In vitro studies confirm that nirmatrelvir is a potent 3CL protease inhibitor of the Omicron variant, suggesting that the drug demonstrates potential therapeutic efficacy against this novel variant as well (https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additionalphase-23-study-resultsn.d.). On December 22, 2021, paxlovid received EUA from the FDA (https://www.pfizer.com/news/press-release/press-release-detail/pfizer-receives-us-fdaemergency-use-authorizationn.d.). Pre-registration clinical trial results demonstrated an 89% reduction in the risk of hospitalization or mortality for COVID-19 compared with placebo. Among patients treated within the first 3 days of symptoms, at day 28 of follow-up, there were 3/389 hospitalizations with no deaths in the paxlovid group compared with 27/385 hospitalizations with 7 deaths in the placebo group (p < 0.0001) (https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oralantiviral-treatment-candidaten.d.). Several clinical trials are ongoing to evaluate the efficacy and safety of paxlovid in patients with COVID-19 (Table 1); an interesting study “Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR)” is evaluating the efficacy and safety of paxlovid administered twice daily for 5 days as a treatment of adults with acute COVID-19 (https://clinicaltrials.gov/ct2/show/study/NCT04960202?term=EPICHR&draw=2&rank=1n.d.). This is a placebo-controlled, double-blind study in patients who are at increased risk of developing severe COVID-19 disease. However, there is a risk of drug interactions in patients on polypharmacy due to the ritonavir component of paxlovid, a particularly potent inhibitor of CYP3A enzymes of the cytochrome P450 system (Hsu et al. 1998). Interaction between ritonavir and CYP3A-dependent drugs may result in increases in the area under the curve of blood concentrations of numerous drugs and possibly increased risk of adverse reactions (Hsu et al. 1998; https://www.fda.gov/media/155050/download2021). Many frail patients such as organ transplant recipients and those on immunosuppressant therapy and paxlovid are at risk for pharmacokinetic drug interactions because drugs such as cyclosporine, tacrolimus, and mTORi (sirolimus and everolimus) are highly dependent on CYP3A metabolism. Other drugs at risk for interactions with ritonavir include statins, calcium channel blockers, and anticoagulants such as warfarin (https://www.fda.gov/media/155050/download2021). Among the first countries in the world to have used large-scale application of the new oral antivirals is the state of Israel. Health authorities there reported that 92% of the 850 patients who took paxlovid showed marked improvement within 3 days; nearly 60% experienced relief of infection symptoms within a day; and, more importantly, none was hospitalized. In patients, paxlovid led to a rapid decrease in fever, headache, and cough. There were few but mild side effects caused by the drug (Fig. 2). To date, there are still few data in the literature on the safety of using the new oral antivirals against COVID-19; a recent meta-analysis considered a total of eight studies, showing that the new oral antivirals were effective in reducing mortality and hospitalization rates in patients with COVID-19. In addition, the antivirals did not increase the occurrence of adverse events, thus showing good overall safety. (Wen et al. 2022b).