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The novel human coronavirus disease COVID-19 has become the fifth documented pandemic since the 1918 flu pandemic. COVID-19 was first reported in Wuhan, China, and subsequently spread worldwide. The coronavirus was officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses based on phylogenetic analysis. SARS-CoV-2 is believed to be a spillover of an animal coronavirus and later adapted the ability of human-to-human transmission. Because the virus is highly contagious, it rapidly spreads and continuously evolves in the human population. In this review article, we discuss the basic properties, potential origin, and evolution of the novel human coronavirus. These factors may be critical for studies of pathogenicity, antiviral designs, and vaccine development against the virus.

Influenza is one of the most common human respiratory diseases, and represents a serious public health concern. However, the high mutability of influenza viruses has hampered vaccine development, and resistant strains to existing anti-viral drugs have also emerged. Novel anti-influenza therapies are urgently needed, and in this study, we describe the anti-viral properties of a Spirulina ( Arthrospira platensis ) cold water extract. Anti-viral effects have previously been reported for extracts and specific substances derived from Spirulina, and here we show that this Spirulina cold water extract has low cellular toxicity, and is well-tolerated in animal models at one dose as high as 5,000 mg/kg, or 3,000 mg/kg/day for 14 successive days. Anti-flu efficacy studies revealed that the Spirulina extract inhibited viral plaque formation in a broad range of influenza viruses, including oseltamivir-resistant strains. Spirulina extract was found to act at an early stage of infection to reduce virus yields in cells and improve survival in influenza-infected mice, with inhibition of influenza hemagglutination identified as one of the mechanisms involved. Together, these results suggest that the cold water extract of Spirulina might serve as a safe and effective therapeutic agent to manage influenza outbreaks, and further clinical investigation may be warranted.

Enterovirus A71 (EV-A71) is an important emerging virus posing a threat to children under five years old. EV-A71 infection in infants or young children can cause hand-foot-and-mouth disease, herpangina, or severe neurological complications. However, there are still no effective antivirals for treatment of these infections. In this review, we summarize the antiviral compounds developed to date based on various targets of the EV-A71 life cycle. Moreover, development of a vaccine would be the most effective approach to prevent EV-A71 infection. Therefore, we also summarize the development and clinical progress of various candidate EV-A71 vaccines, including inactivated whole virus, recombinant VP1 protein, synthetic peptides, viral-like particles, and live attenuated vaccines.

We provide the first evidence for the role of ACSL4 in enterovirus replication organelle formation. Moreover, both enteroviruses and coronaviruses induce ferroptosis via ACSL4. These findings establish a novel regulatory mechanism for viral replication. The inhibition of ACSL4 by ferroptosis inhibitors can reduce viral yields of enteroviruses and coronaviruses, including SARS-CoV-2, implying that ACSL4-mediated ferroptosis is a promising therapeutic target for viral diseases. Enterovirus infections can cause severe complications, such as poliomyelitis, encephalitis, myocarditis, meningitis, neurological pulmonary edema, and even death. Here, we used genome-wide CRISPR screens to gain new insight into the mechanism by which enteroviruses co-opt host pathways to potentiate replication and propagation. We found that acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) is involved in viral replication organelle formation. ACSL4 is a key component of ferroptosis, an iron-dependent, nonapoptotic programmed cell death. Our results indicated that enteroviruses and coronaviruses can induce ferroptosis via ACSL4. Most importantly, ferroptosis inhibitors, including two FDA-approved drugs, rosiglitazone (ROSI; ACSL4 inhibitor) and pioglitazone (PIO; ACSL4 inhibitor), decreased the viral load of human enteroviruses and coronaviruses, suggesting that ACSL4 is a target for counteracting viral infection. IMPORTANCE We provide the first evidence for the role of ACSL4 in enterovirus replication organelle formation. Moreover, both enteroviruses and coronaviruses induce ferroptosis via ACSL4. These findings establish a novel regulatory mechanism for viral replication. The inhibition of ACSL4 by ferroptosis inhibitors can reduce viral yields of enteroviruses and coronaviruses, including SARS-CoV-2, implying that ACSL4-mediated ferroptosis is a promising therapeutic target for viral diseases.

Most individuals infected with or vaccinated against COVID-19 develop antigenic neutralizing immunoglobulin G (IgG) antibodies against the SARS-CoV-2 spike protein. Although neutralizing antibodies are biomarkers of the adaptive immune response, their mere presence is insufficient to explain the protection afforded against the disease or its pathology. IgG exhibits other secondary effector functions that activate innate immune components, including complement, natural killer cells, and macrophages. The affinity for effector cells depends on the isotypes and glycosylation of IgG antibodies. The anti-spike IgG titer should be sufficient to provide significant Fc-mediated effects in severe COVID-19, mRNA, and protein subunit vaccinations. In combination with aberrant effector cells, pro-inflammatory afucosylated IgG1 and IgG3 may be detrimental in severe COVID-19. The antibody response of mRNA vaccines leads to higher fucosylation and a less inflammatory IgG profile, with a long-term shift to IgG4, which is correlated with protection from disease.

Enterovirus 71 (EV71) induces apoptosis to promote viral particle release. Earlier work showed that EV71 utilizes its 3C protease to induce apoptosis in a caspase-3-dependent pathway, though the mechanism is unknown. However, work from Vagner, Holcik and colleagues showed that host protein heterogeneous ribonucleoprotein A1 (hnRNP A1) binds the IRES of cellular apoptotic peptidase activating factor 1 (apaf-1) mRNA to repress its translation. In this work, we show that apaf-1 expression is essential for EV71-induced apoptosis. EV71 infection or ectopic expression of 3C protease cleaves hnRNP A1, which abolishes its binding to the apaf-1 IRES. This allows IRES-dependent synthesis of apaf-1, activation of caspase-3, and apoptosis. Thus, we reveal a novel mechanism that EV71 utilizes for virus release via a 3C protease-hnRNP A1-apaf-1-caspase-3-apoptosis axis.

Children are susceptible to severe or fatal enterovirus 71 (EV71) infections. We aimed to evaluate the efficacy, safety, and immunogenicity of EV71vac, an aluminium phosphate-adjuvanted inactivated EV71 vaccine in children aged 2–71 months. We did a randomised, double-blinded, placebo-controlled, phase 3 trial at five hospitals in Taiwan and two in Vietnam. Children aged 2–71 months were stratified by country and age, and randomly assigned (1:1) to receive two doses of EV71vac or placebo via intramuscular injection 56 days apart. Children aged 2–23 months received a third booster dose on day 366. The primary endpoint was the clinical efficacy of the total vaccinated cohort against EV71-associated diseases during the follow-up period, from 14 days after the second dose to when 15 cases of EV71 infections were confirmed in the per-protocol population. Our safety analysis included all participants who received at least one dose of EV71vac. This trial is registered with ClinicalTrials.gov, NCT03865238, and is complete. Between April 23 and Dec 25, 2019, of 3663 children assessed, 3061 were randomly assigned, of whom 3049 were vaccinated: 1521 children in the EV71vac group and 1528 in the placebo group. By May 20, 2021, our primary efficacy analysis included 2959 children, with 1476 children in the EV71vac group and 1483 children in the placebo group. The vaccine efficacy of EV71vac was 96·8% (95% CI 85·5–100) against EV71 associated diseases (p<0·0001). The percentage of participants who reported solicited adverse events were similar in both groups: 865 (56·9%) in the EV71vac group and 852 (55·8%) in the placebo group. Almost all reported solicited adverse events were mild and self-limited. EV71vac is safe, well-tolerated, and highly effective in preventing EV71 associated diseases in children aged 2–71 months. Medigen Vaccine Biologics and A+ Industrial Innovative R&D Program of the Ministry of Economic Affairs, Taiwan.

Serological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 3.5% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-receptor-binding domain (RBD), three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two recovered patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. Finally, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.

Enterovirus A71 (EV-A71) is a major causative agent of hand, foot, and mouth disease (HFMD) and herpangina. Moreover, EV-A71 infection can lead to neurological complications and death. Vaccination is the most efficient way to control virus infection. There are currently three inactivated, whole EV-A71 vaccines licensed by the China NMPA (National Medical Products Administration). Several other types of vaccines, such as virus-like particles and recombinant VP1 (capsid protein), are also under development. In this review, we discuss recent advances in the development of EV-A71 vaccines.

Heterologous prime-boost COVID-19 vaccine strategy may facilitate mass COVID-19 immunization. We reported early immunogenicity and safety outcomes of heterologous immunization with a viral vector vaccine (ChAdOx1) and a spike-2P subunit vaccine (MVC-COV1901) in a participant-blinded, randomized, non-inferiority trial (NCT05054621). A total of 100 healthy adults aged 20–70 years having the first dose of ChAdOx1 were 1:1 randomly assigned to receive a booster dose either with ChAdOx1 ( n  = 50) or MVC-COV1901 ( n  = 50) at an interval of 4–6 or 8–10 weeks. At day 28 post-boosting, the neutralizing antibody geometric mean titer against wild-type SARS-CoV-2 in MVC-COV1901 recipients (236 IU/mL) was superior to that in ChAdOx1 recipients (115 IU/mL), with a GMT ratio of 2.1 (95% CI, 1.4 to 2.9). Superiority in the neutralizing antibody titer against Delta variant was also found for heterologous MVC-COV1901 immunization with a GMT ratio of 2.6 (95% CI, 1.8 to 3.8). Both spike-specific antibody-secreting B and T cell responses were substantially enhanced by the heterologous schedule. Heterologous boosting was particularly prominent at a short prime-boost interval. No serious adverse events occurred across all groups. The findings support the use of heterologous prime-boost with ChAdOx1 and protein-based subunit vaccines. Public safety concern of the ChAdOx1 vaccine has led to an alternative immunisation strategy against SARS-CoV-2, with this heterologous schedule widely adopted and officially recommended in many countries. Here, the authors report the immunogenicity and safety outcomes of heterologous prime-boost immunisation with ChAdOx1 and a spike-2P subunit vaccine in a single-blinded, randomised trial.