key: cord-0879926-8u3f5osq authors: Chen, Ji‐Ming title: Should the world collaborate imminently to develop neglected live‐attenuated vaccines for COVID‐19? date: 2021-09-21 journal: J Med Virol DOI: 10.1002/jmv.27335 sha: fc0e34080e5fedc211ab182f33ea562ee9077775 doc_id: 879926 cord_uid: 8u3f5osq The rapid spread of the Delta variant suggests that SARS‐CoV‐2 will likely be rampant for months or years and could claim millions of more lives. All the known vaccines cannot well defeat SARS‐CoV‐2 due to their limited efficacy and production efficiency, except for the neglected live‐attenuated vaccines (LAVs), which could have a much higher efficacy and much higher production efficiency than other vaccines. LAVs, like messiahs, have defeated far more pathogenic viruses than other vaccines in history, and most current human vaccines for viral diseases are safe LAVs. LAVs can block completely infection and transmission of relevant viruses and their variants. They can hence inhibit the emergence of vaccine‐escape and virulence‐enhancing variants and protect immunologically abnormal individuals better in general. The safety of COVID‐19 LAVs, which could save millions of more lives, can be solidly guaranteed through animal experiments and clinical trials. The safety of COVID‐19 LAVs could be greatly enhanced with intramuscular or oral administration, or administration along with humanized neutralizing monoclonal antibodies. Together, extensive global collaboration, which can greatly accelerate the development of safe COVID‐19 LAVs, is imminently needed. 59%. 5 Their efficacy will likely decline further due to the decrease of antibody titers in recipients and the accumulation of more mutations in SARS-CoV-2 over time. 3 All the marketed COVID-19 vaccines have relatively low production efficiency, compared to the huge demand for combating the pandemic. 1, 4 Consequently, as of 30 August 2021, vaccination coverage in many countries has not reached 10%. 1 Particularly, although COVID-19 mRVs are more efficacious than other marketed COVID-19 vaccines, it should take years for the world to produce enough COVID-19 mRVs for most people on the globe. 1, 4 Their stringent requirements for storage and high prices also impede their global application. 4 In genomic sequences, SARS-CoV-2 is phylogenetically close to, but also distinct from, SARS-CoV-1, the virus causing the severe acute respiratory syndrome (SARS) outbreak in 2003. 6 They share the same receptor and cause similar diseases, which suggests that SARS-CoV-2 is flexible enough to change its genomes. Therefore, the emergence of vaccine-escape variants of SARS-CoV-2 is likely unavoidable, if their transmissions are only partially blocked by vaccination. Hence, the world will likely fall into the disastrous and costly cycle of repeated emergence of vaccine-escaping variants followed by repeated updating of vaccines. 7 Similar scenarios have occurred in the mass vaccination for influenza and other viral diseases. 8, 9 Together, SARS-CoV-2 and vaccines could have a seesaw relationship, namely only one side could win in the long run ( Figure 1 ). After the COVID-19 pandemic, SARS-CoV-2 should cause much fewer deaths annually due to increased human herd immunity against the virus. 10 However, variants of SARS-CoV-2 could cause seasonal COVID-19 outbreaks, which could be parallel to seasonal influenza in severity and a little severer than the common cold, due to the intrinsic pathogenesis of SARS-CoV-2. 6,7 Therefore, seasonal COVID-19 could cause annually over 200 000 deaths, even if some people are vaccinated with partially efficacious COVID-19 vaccines, parallel to the fact that seasonal influenza annually causes 290 000−650 000 deaths, 8 even if some people are vaccinated with partially efficacious influenza vaccines. Meanwhile, SARS-CoV-2 could become highly virulent and cause millions of deaths again in the future at a low possibility, due to rare random genomic mutations, like the fact that multiple RNA viruses, for example, avian influenza viruses, 11 porcine reproductive and respiratory syndrome, 12 and porcine epidemic diarrhea virus (a coronavirus), 13 (Table 1) . 7, 9 Second, LAVs can be much more efficacious than other vaccines. In structure and mechanism, safe LAVs are akin to perfect mRVs or vector vaccines, and they uniquely produce multiple, endogenous, and relatively large quantities of viral antigens (Table 2) . 4, 7, 9 Usually exogenous antigens can induce only humoral immunity, while endogenous antigens can induce both humoral immunity and cell- Table 1 controlled with LAVs have been identified in the past decades. 7,9 Therefore, from a panoramic viewpoint, these effects of LAVs can provide much better The potential seesaw game between SARS-CoV-2 and vaccines in the long run Second, it is difficult to obtain safe LAV seeds. Traditionally, LAV seeds were from the viruses phylogenetically close to the targeted pathogenic viruses (e.g., the seed of smallpox LAV), or attenuated through serial passage in heterogeneous hosts (e.g., the seed of measles LAV). 9 identified and treated in time. 7 Additionally, these patients could be infected naturally with wild-type SARS-CoV-2, if they have not been inoculated with a fully efficacious COVID-19 vaccines. 16, 17 The safety of COVID-19 LAVs could be further enhanced through intramuscular injection or oral administration, to avoid the risk of vaccine-induced pneumonia. This mechanism has been applied safely for 40 years for preventing adenovirus-associated acute respiratory disease in US recruits, through oral administration of enteric-coated capsules containing wild-type adenoviruses, to bypass the pathogenesis site of the lungs. 21 The safety of COVID-19 LAVs could be further enhanced if they are inoculated along with neutralizing antibodies, and the LAVs thereby become live immune-complex vaccines (LICVs). 22 LICVs could be as highly efficacious as LAVs partially due to immune opsonization, and much safer than LAVs due to neutralization of the antibodies, and could provide protection immediately after vaccination. 22 it was difficult to produce vast safe neutralizing antibodies from human sera for human LICV production. Now, the production of humanized neutralizing monoclonal antibodies has become highly efficient, and hence human LICVs could be rejuvenated. 25 Together, possibly only COVID-19 LAVs could well defeat SARS-CoV-2, and their safety can be well guaranteed, for multiple reasons ( WHO Coronavirus disease (COVID-19) pandemic Effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infection among frontline workers before and during B.1.617.2 (Delta) variant predominanceeight U.S. locations Effectiveness of Pfizer-BioNTech and Moderna Vaccines in preventing SARS-CoV-2 infection among nursing home residents before and during widespread circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant-National Healthcare Safety Network COVID-19 vaccines Efficacy of inactivated SARS-CoV-2 vaccines against the Delta variant infection in Guangzhou: a testnegative case-control real-world study Genomic feature analysis of Betacoronavirus provides insights into SARS and COVID-19 pandemics Potential for elimination of SAR-CoV-2 through vaccination as inspired by elimination of multiple influenza viruses through natural pandemics or mass vaccination Vaccine Analysis Strategies, Principles, and Control Immunological characteristics govern the transition of COVID-19 to endemicity Control of avian influenza in China: strategies and lessons Molecular detection and characterization of highly pathogenic porcine reproductive and respiratory syndrome virus from a natural outbreak in wild pigs Evolution, antigenicity and pathogenicity of global porcine epidemic diarrhea virus strains Scalable live-attenuated SARS-CoV-2 vaccine candidate demonstrates preclinical safety and efficacy Evaluation of the attenuation, immunogenicity, and efficacy of a live virus vaccine generated by codon-pair bias de pandemic H1N1 influenza virus, in ferrets Poliomyelitis vaccination: past, present and future Epidemiology of poliomyelitis in the United States one decade after the last reported case of indigenous wild virus-associated disease Evidence of recombination of vaccine strains of lumpy skin disease virus with field strains, causing disease Could live attenuated vaccines better control COVID-19? Vaccine Animal coronavirus vaccines: lessons for SARS Safety evaluation of adenovirus type 4 and type 7 vaccine live, oral in military recruits Live unattenuated vaccines for controlling viral diseases, including COVID-19 Comparative evaluation of HVT-IBD vector, immune complex, and live IBD vaccines against vvIBDV in commercial broiler chickens with high maternally derived antibodies Human-IgG-neutralizing monoclonal antibodies block the SARS-CoV-2 infection How to cite this article: Chen J-M. Should the world collaborate imminently to develop neglected live-attenuated vaccines for COVID-19 The author declares that there are no conflict of interests. This article does not contain the participation of animals and humans. The data that support the findings of this study are available from the corresponding author upon reasonable request.