COVID-19 has posed an unprecedented threat to the health and economy globally since its first detection in December 2019 with more than 435 million cases and 5.9 million deaths (as of February 27,2022). The impressive co-operation between academic institutions, pharmaceutical and biotech companies, and governmental organisations has resulted in never-before-seen progress on many fronts. Especially, vaccine development has been swift with the Emergency Use Authorisation (EUA) of both adenovirus- and mRNA-based vaccines and the FDA approval of the BNT162b2 mRNA vaccine in August 2021. The development of efficient antiviral drugs has turned out to be more difficult. For this reason, one approach has been to develop repurposed drugs, previously approved for viral and tropical diseases.
The mRNA-based BNT162b2 (Pfizer/ BioNTech) and mRNA-1273 (Moderna) SARS-CoV-2 vaccines both express the SARS-CoV-2 Spike (S) protein as the antigen. Good safety and protection have been achieved in animal models and 95 per cent and 94.1 per cent vaccine efficacy, respectively, obtained in clinical trials (Polack et al., 2020; Baden et al., 2021). Today, a third vaccination dose has been recommended and also executed in several countries due to waning of immune responses with time and the appearance of novel potentially more transmissible and virulent SARS-CoV-2 variants. In the context of adenovirusbased SARS-CoV-2 vaccines, four vaccine candidates all based on the delivery of the full-length S protein have received EUAs in at least some countries (Lundstrom, 2021). The ChAdOx1 nCoV-19 (AstraZeneca/University of Oxford) is based on a chimpanzee adenovirus and requires two immunisations to reach vaccine efficacy (Voysey et al., 2021). In contrast, a single dose of the Ad26. COV2.S (Johnson & Johnson/Jansen Pharmaceuticals) vaccine based on the human adenovirus serotype 26 provided strong immune response and protection in clinical trials (Sadoff et al., 2021). The Russian made Sputnik V vaccine rAd26-S/rAd5-S utilises a strategy of prime vaccination with an adenovirus serotype 26 vector followed by a booster vaccination with the adenovirus serotype 5 to avoid immune responses against the adenovirus vector, which can reduce expression levels and immunogenicity (Logunov et al., 2021). Finally, the Ad5-S-nb2 (CanSinoBIO) vaccine candidate based on the adenovirus serotype 5 showed efficacy in clinical trials and has received EUA in China (Zhu et al., 2020).
Although the current vaccines have proven efficacious against SARS-CoV-2 in general, concern has been raised about the longevity of the protection and the discovery of some breakthrough infections, where fully vaccinated individuals developed COVID-19. Another concern relates to SARS-CoV-2 variants/mutants, which have appeared frequently. Variants of concern (VoC) such as alpha, beta, gamma and especially delta have been proposed to be more transmissible and virulent than the original SARSCoV-2 Wuhan strain. Recently, the novel omicron strain was declared to be at least 10 times more infectious than any previously discovered variant albeit based on an artificial intelligence (AI) model (Chen et al., 2021) and not evaluated in in vitro or in vivo settings. Bioinformatics approaches have indicated that the omicron shows lower pathogenicity but higher antigenicity than the Wuhan wildtype or the delta and gamma variants (Barh et al., 2022). The SARSCoV-2 VoC therefore pose a threat to the protection offered by current COVD-19 vaccines. Recent preliminary evaluations have suggested that for example the mRNA-based vaccines provide approximately 40 per cent protection against the omicron variant after two doses, whereas three doses are expected to provide excellent protection.
Especially mRNA-based vaccines are prone to degradation meaning that the BNT162b2 and the mRNA-1273 vaccines need to be stored and transported at -80°C and -20°C, respectively. Adenovirus-based vaccines demand less stringent conditions and can be stored for up to two weeks at +4°C. The logistics of transportation, distribution, and administration of COVID-19 vaccines have presented a serious problem for achieving the maximum global vaccine coverage. As of February 27, 2022, 10.7 billion doses of COVID-19 vaccines have been administered globally and 62.7 per cent of the world population has received at least one dose. The low rate of only 12.3 per cent of people vaccinated in developing countries is of great concern.
Another complication related to vaccines has been the discovery of rare cases of vaccine-induced thrombotic thrombocytopenia (VITT) after vaccinations with both adenovirus- and mRNAbased vaccines. However, the rate is by far lower than seen in COVID-19 patients and should not discourage vaccination efforts. Unfortunately, the anti-vaccine campaign based on misinformation, disinformation, and even conspiracy theories have further hampered the progress of vaccination worldwide.
In parallel to vaccine development, extensive unprecedented research and development of antiviral drugs against COVID-19 have been conducted. Engineering of efficacious antiviral drugs has been demanding, and due to the urgency, existing antiviral and parasitic drugs have been repurposed for COVID-19 in parallel to the discovery of novel antivirals. In this context, drugs such as remdesivir, chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir, and ivermectin have been repurposed for COVID-19. Despite early promising findings from preclinical studies and preliminary clinical trials, in most cases no significant reduction in mortality, time to fever resolution, or clinical benefits have been observed compared to standard of care. For these reasons, neither hydroxychloroquine nor ivermectin have been approved for COVID-19 treatment by the FDA. However, the FDA approved in October 2020 the use of remdesivir for the treatment of hospitalised COVID-19 patients. Very recently, two oral antivirals, molnupiravir (Merck) and paxlovid (Pfizer) were developed for COVID-19. Molnupiravir inhibits SARS-CoV-2 by widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase (RdRp).Two phase I clinical trials demonstrated a significant reduction in both hospitalisation and death rates in patients with mild COVID-19 disease (Singh et al., 2021). Although molnuvirapir was approved in the UK, its lower-than-expected efficacy of 30 per cent reduced risk of hospitalisation the approval by the FDA was first put on hold (Kozlov 2021), but then received an EUA on December 23, 2021 Kozlov 2021). Paxlovid is a 3C-like protease (3CLpro) inhibitor, which in combination with ritonavir disrupts the SARSCoV-2 replication. Preliminary data from clinical trials indicated that the risk of COVID-19 associated hospitalisation or death was reduced by 89 per cent (www.pharmaceutical-technology.com/features/paxlovid-pfizer-covid-19-pill/). Unfortunately, paxlovid was inaccurately described as a merely “repackaged” version of ivermectin although it is not structurally related or similar to ivermectin (Bloom 2021). Paxlovid is significantly more potent with a 10,000-times lower IC50 value. The FDA granted Paxlovid an EUA on December 22, 2021.
Several monoclonal antibodies such as LY-CoV555named bamlanivimab (Ely-Lilly) and the monoclonal antibody cocktail REGN-COV2 (Regeneron) consisting of REGN10987 (imdevimab) and REGN10933 (casirivimab) have demonstrated good efficacy, but the requirement of high-dose intravenous injections make their therapeutic utilisation less convenient. LY-CoV555 received EUA by the FDA in November 2020 for treatment of mild to moderate COVID-19 in adult and paediatric patients. Moreover, REGN-COV2 was given EUA as prevention in adults and paediatric individuals, who are at high risk of developing severe COVID-19.
Most of the currently available drugs developed for treatment of COVID- 19 patients only provide modest efficacy in case studies and clinical trials. Although some drugs such as remdesivir and favipiravir have been approved by the FDA for limited applications in mainly hospitalised COVID-19 patients more efficient drugs are needed. Recently the orally administered RdRp inhibitor molnuvirapir and the 3CLpro inhibitor paxlovid have been presented as “gamechangers” in the fight against COVID-19, but especially the former showed lower-than-expected efficacy in clinical trials. Monoclonal antibodies have demonstrated efficacy, but the need of high doses of intravenous administration has made their application complicated and expensive.
Interestingly, repurposed and novel antiviral COVID-19 drugs have not been subjected to the same unsubstantiated and unprofessional scepticism, which has been seen for vaccines. Repurposed drugs such as chloroquine, hydroxychloroquine and ivermectin have been too quickly announced as the “magic bullets” or “miracle cures” without being properly evaluated in large, well-planned and executed clinical trials. Illogically it has been stated that these drugs have been used in humans for decades without any safety issues. However, treatment of malaria and worm-diseases should not be compared to therapeutic interventions against COVID-19, which was dramatically experienced for hydroxychloroquine, resulting in a higher risk of ECG abnormalities/arrhythmia.
In the context of vaccines, the race to vaccinate the global population will continue in 2022 for sure. The appearance of highly transmissible VoCs quickly becoming dominant worldwide and their potentially increased resistance to vaccines have required new strategies. In one strategy, booster doses of existing vaccines aim at enhancing immunogenicity leading to better protection. Another strategy comprises the adjustment of existing vaccines to adapt them more efficiently the VoC and in parallel to develop totally new vaccine candidates. The majority of COVID-19 vaccine development has focused on the SARS-CoV-2 S protein as an antigen. In some unique cases other SARS-CoV-2 proteins such as the nucleoprotein (N) or the membrane protein (M) have been targeted. It would be useful to develop pan-vaccines targeting a broader range of the SARS-CoV-2 structure to avoid the continues “catch-up game” with the new variants harbouring a modified S protein structure. So far, all approved COVID-19 vaccines are based on intramuscular administration. However, adenovirus- and influenza virus-based vaccine candidates have been subjected to intranasal administration in animal models. The influenza virus-based intranasal COVID-19 vaccine candidate is currently in phase III in China. In the context of mRNA-based vaccines the stability has been improved for the new liposome nanoparticle encapsulated SARS-CoV-2 S RBD mRNA (ARCoV) vaccine, which provided protection in mice and due to temperature stability could be stored at room temperature for one week.
COVID-19 drug research and development of repurposed and novel drug candidates has continued. Inhaled corticosteroids have proven beneficial for dealing with viral infections and their use by patients with stable asthma or chronic obstructive pulmonary disease (COPD), should also reduce the risk of SARS-CoV-2 infections. Moreover, it was demonstrated in patients with moderate to severe COVID-19 that low dose treatment with prednisolone was superior in shortening the length of hospital stay compared to lopinavir/ritonavir treatment (Ghanei et al., 2021).
The development of monoclonal antibodies is also an area of high potential. However, the need of intravenous administration of expensive high doses of monoclonal antibodies has put limitations on their applicability for large-scale use for COVID-19 treatment. However, a novel approach of DNA plasmid-based in vivo monoclonal antibody expression has generated peak plasma levels of 270 ng/ml showing superiority to protein-based administration (Vermeire et al., 2021). Obviously, this approach can also be applied for the expression of monoclonal antibodies targeting SARS-CoV-2.
Finally, application of mesenchymal stem cells (MSCs) for therapeutic intervention have produced some promising results making it an attractive technology also for COVID-19 treatment. Preliminary findings indicated that MSCs can be effective in treatment of acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2.
The question everybody is asking is when will the pandemic end? Will SARS-CoV-2 disappear like SARS-CoV did within two years after the outbreak of SARS? The world has recently experienced the fifth wave of COVID-19. Certainly, we are better off now than at the beginning of the pandemic. We have safe and efficacious vaccines, which will eventually need second and third generation versions. Antiviral drug development is moving forward at full speed. We have to some extent learned to live with the pandemic although it has been hard both physically and psychologically. Can we see the light at the end of the tunnel? For certain to cite Winston Churchill: “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning”.
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