key: cord-0778136-aotexfs9
authors: Chen, Ji‐Wang; Chen, Ji‐Ming
title: Potential of live pathogen vaccines for defeating the COVID‐19 pandemic: history and mechanism
date: 2020-04-22
journal: J Med Virol
DOI: 10.1002/jmv.25920
sha: f20d62c1d5cb85d58082b177d62d7bdf9c4b7fff
doc_id: 778136
cord_uid: aotexfs9

The whole world has entered a terrible crisis with a huge and increasing amount of human deaths and economic loss in fighting the pandemic of COVID‐19 caused by the novel coronavirus termed SARS‐CoV‐2. The live pathogen vaccine (LPV) strategy, which originated in ancient China for fighting smallpox, has been applied successfully in the USA military recruits for decades to control acute respiratory diseases caused by types 4 and 7 adenoviruses. This strategy has also been widely employed in veterinary medicine. These facts suggest a fast way out of the current pandemic crisis, namely that SARS‐CoV‐2 could be directly used as a live vaccine. Beyond the two traditional mechanisms to guarantee the LPV's safety (SARS‐CoV‐2 is not highly pathogenic; the LPV is inoculated bypassing the respiratory sites of pathology), three novel mechanisms to further ensure the LPV's safety are available (the virus replication is inhibited with early use of an antiviral drug; symptomatic LPV recipients are cured with convalescent plasma; the LPV is inoculated in hot seasons). This LPV strategy has multiple potential advantages over other options, and could reduce greatly the morbidity and mortality as well as economic loss caused by the pandemic. The safety and efficacy of this strategy should be investigated strictly using animal experiments and clinical trials, and even if the experiments and trials all support the strategy, it should be implemented with enough cautiousness. This article is protected by copyright. All rights reserved.

The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel coronavirus termed SARS-CoV-2 is spreading rapidly worldwide. 1 Over two million cases have been confirmed, and approximately 6% of them were fatal. 1 Multiple types of vaccines are under urgent development, and some of them have entered clinical trials. [2] [3] [4] [5] [6] [7] Because no vaccine against coronavirus has been widely used in humans, experiences are scanty regarding the safety and efficacy of vaccination against COVID-19. Moreover, development of vaccines against SARS CoV, which caused a deadly outbreak in the 2000s, encountered much difficulty. [3] [4] [5] [6] [7] The difficulty has also manifested in research of coronavirus vaccines in veterinary medicine. 8 First, coronaviruses can escape the immunity induced by inactivated vaccines or recombinant protein vaccines through rapid evolution. 8 Second, live attenuated vaccines of coronaviruses can regain its virulence through serial passages in cell culture or in vivo. 9 Third, sometimes vaccination in animals and humans may aid rather than inhibit pathogenesis of the targeted viruses. This phenomenon of vaccination enhancement may result from antibody-dependent enhancement, a process in which specific antibodies aid the infection of the targeted virus, or cellbased enhancement, a process involving allergic inflammation caused by This article is protected by copyright. All rights reserved.

immunopathology. 5 Vaccination enhancement has been observed in the research of SARS vaccines and may be a pitfall in the development of COVID-19 vaccines. [3] [4] [5] [6] [7] [8] Due to the difficulty in vaccine development, it is possible that no safe and effective vaccines shall be marketed before 2022 when the pandemic shall likely end worldwide, although various vaccines against COVID-19 are under development with unprecedented rapidity. 3, 10 This possibility puts the whole world in a terrible crisis, and most countries have to maintain the blocking-and-curing strategy for months, which is too costly with too many deaths, too much uncertainty, and too extensive chaos.

Bold strategies with rationality were more effective than orthodox ones in multiple wars in history. Similarly, the live pathogen vaccine (LPV) strategy analyzed in this paper is bold with rationality, and could be a fast way out of the pandemic crisis.

Infectious acute respiratory disease (ARD) is prevalent in US military recruits. 11 The disease persists for 310 days with fever, cough, sore throat, nasal discharge, headache, and fatigue. The majority of these ARD cases are caused by adenovirus, usually types 4 and 7 and less frequently types 3, 14 and 21. 12 Historically, adenovirus has infected up to 80% of recruits, 20% of whom may be hospitalized; 90% of hospitalized cases of pneumonia in recruits have been attributed to adenovirus infections. 12 Inactivated vaccines against adenoviruses were first investigated in the military, and they showed variable degree of protection. 13 Concerns over the oncogenic potential of simian virus 40 contaminated in the cell lines used for growth of the adenoviruses further hampered the application of the inactivated vaccines. 11 Recently, the oncogenic potential of simian virus 40 contaminated in the cell lines was found to be unsubstantiated. 14 Adenoviruses can also replicate in the intestinal tract. 13 This suggested that it might be possible to selectively infect the intestinal tract to bypass the respiratory tract where pathologic changes most often occur. 13 Subsequent attempts at intestinal infection with live wild pathogenic adenovirus were found to yield high rates of seroconversion with few adverse effects, leading to the birth of the LPV against human infectious diseases. 12 Initial application of the adenovirus LPV This article is protected by copyright. All rights reserved.

resulted in great reduced type 4 adenovirus infections and increased type 7 adenovirus infections. 12 Therefore, the bivalent LPV containing types 4 and 7

replaced the previous LPV only containing type 4 adenovirus. 12, 13, 15 Routine vaccination with the bivalent LPV in US recruits began in 1971, and rates of adenovirus-associated ARD were reduced by up to 96%. 13 Despite their efficacy, the LPV vaccination was suspended in 1999 due to commercial reasons, and adenovirus-associated ARD in military recruits resurged. In October 2011, the bivalent LPV was universally administered to military recruits again, and adenovirusassociated ARD cases decreased by 99.66% among recruits. 15 Hundreds of years ago, the LPV of smallpox virus was widely inoculated nasally in ancient China to prevent smallpox. The inoculation was effective although it caused a disease milder than the natural infection. 16 Later, this inoculation was replaced with the safer vaccine based on cow poxvirus. Like the fight against smallpox, the LPV strategy was widely used in veterinary medicine to reduce morbidity and mortality of rinderpest and swine fever in the history before live attenuated vaccines were developed. 17 In the 1980s, rotavirus caused diarrhea in pigs in China. The LPV of swine rotavirus was employed for years because pigs did not show symptoms and yielded excellent immunity after they were intramuscularly injected with pathogenic swine rotavirus to bypass the intestine of pathology. 18 Currently, LPVs of moderate virulence continue to be used in poultry worldwide, to induce strong immunity against avian infectious laryngotracheitis, Newcastle disease, and infectious bursal disease. 19,20

The safe and successful prevention of adenovirus-associated ARD in the USA recruits suggests, not proves, that the LPV strategy could pave a way out of the terrible crisis of the coronavirus pandemic. In theory, five mechanisms can be employed to guarantee the safety of the LPV of SARS-CoV-2.

First, SARS-CoV-2 itself is not highly pathogenic as compared with rabies virus, human immunodeficiency virus, Ebola virus, Nipah virus, and SARS CoV. Most natural infections of SARS-CoV-2 are of no or mild symptoms, and the virus does not persist in most cases. 21, 22 Second, like the adenovirus LPV, the LPV of SARS-CoV-2 is intestinally inoculated through enteric-coated capsules, in order to move the battlefield from the lungs to Accepted Article the intestine. The outcome of the viral infection is determined by the battle between the immune system and the virus. The virus can kill immune cells and other cells through its replication or using its viruporins, and the immune system can kill the virus using the chemokines, cytokines, complement factors, antibodies, macrophages, NK cells, and Cytotoxic T lymphocytes. 9 The immunity of the intestine is likely stronger than that of respiratory organs, because the intestine has been 

with COVID-19. [28] [29] [30] [31] In theory, its efficacy should be better in curing mild patients upon onset of symptoms. 32 Importantly, many recipients of the LPV vaccine or CP are potential candidates for donating CP, and this could ensure the supply of CP for the LPV strategy.

Fifth, mass vaccination of the LPV is conducted in hot seasons when other respiratory infections are much rarer than in cold seasons. This could reduce mixed infections and thus further safeguard the safety of the LPV strategy.

Importantly, inoculation of the LPV does not increase the risk to the world, because otherwise the virus shall also spread to every corner of the world, and almost every one shall contact it for one or more times.

The safety and efficacy of the LPV strategy theoretically analyzed above should be carefully confirmed using robust animal experiments and clinical trials. immune to the challenge of SARS-CoV-2? Is the boost immunization needed to secure the solid immunity against the virus? Some of these experiments can be conducted rapidly using golden Syrian hamsters or ferrets rather than rhesus monkeys. 33, 34 Second, clinical trials could be conducted in a special approach involving two parts. The first part is to investigate whether early use of an antiviral medication upon infection confirmation and early use of CP upon symptom onset could reduce greatly the morbidity and mortality of COVID-19. The second part is to examine whether inoculation of the LPV bypassing the respiratory sites could also reduce greatly the morbidity and mortality.

The current prevalent natural infections of the virus make clinical trials relatively readily available to implement the first part of the clinical trials. With informed consent, high-risk uninfected persons are monitored twice a day to determine when This article is protected by copyright. All rights reserved. Accepted Article they will be infected by SARS-CoV-2. A clinically approved antiviral medication is administrated to some of these uninfected people once they are found to be infected with SARS-CoV-2, and 50 mL CP is administrated to some of these infected 

The LPV, if supported by animal experiments and clinical trials, could be marketed earlier than other types of vaccines. This is because the animal experiments and the first part of the clinical trials could be conducted simultaneously and completed within two months, and the second part of the clinical trials could be completed in the following two months. Global collaboration could further ensure that these experiments could be completed within four months.

The LPV strategy is of multiple advantages over the current "blocking and curing" strategy, as it could dramatically reduce the morbidity and mortality and reduce the time for establishing herd immunity against the pandemic virus. It could This article is protected by copyright. All rights reserved.

provide safety for the society to lift various quarantine restrictions, restore social order, production, consumption, and freedom in various respects. Therefore, the LPV strategy could have great significance in public health, social order and economy.

If the world keeps the present blocking-and-curing strategy before 2022, almost all the people worldwide shall catch the virus, and approximately 20% of them shall manifest moderate or severe symptoms, and the case fatality rate (CFR) is approximately 4%. Therefore, the morbidity and mortality of the total population due to COVID-19 is approximately 20% and 0.8%, respectively. 21, 22 Because the adenovirus LPV with a single safety guarantee reduced adenovirus-associated ARD cases by 99.66% among the USA recruits, 15 we presume that the LPV strategy of SASR-CoV-2 with five safety mechanisms could reduce the morbidity by 90% to 2% and the CFR by 90% to 0.4%, and thus the mortality could decline by 99% to 0.008%, as compared with natural infections.

As compared with other types of vaccines, the LPV of SARS-CoV-2 could also have its distinct advantages, beyond its potential rapid evaluation and earlier marketing. First, the LPV could be rapidly supplied to many people, because the virus grows rapidly in cell culture, and less viruses are needed for the LPV to vaccinate a person, as compared with for the inactivated vaccine which also employs cell culture of the pathogen virus. Second, if the LPV is administrated with enteric-coated capsules, the vaccination process is simpler than vaccination of other vaccines, because no syringe, needle, or other adjunct equipment is needed. Third, usually the LPV could induce stronger acquired immunity against SARS-CoV-2 than other vaccines, especially in mucosal immunity which is paramount for prevention of respiratory viruses. Fourth, some live vector virus vaccines have the potential of carcinogenicity and mutagenicity, 37 and these potentials have not been identified in live coronaviruses. Fifth, some live attenuated coronaviruses can regain their virulence, 9 and this is not a concern of the LPV strategy. Sixth and importantly, other types of vaccines have the potential to accelerate mutation and diversification of the targeted virus to escape the induced immunity, 38 while mass inoculation of the single strain of the LPV, the immunity induced by the LPV, and the medications to inhibit the replication of the LPV, all have the potential to inhibit the replication of diversified SARS-CoV-2 circulating in different regions of the world.

Taken together, the LPV could induce stronger immunity, establish herd immunity more rapidly, and inhibit indirectly the viral mutation and diversification. This article is protected by copyright. All rights reserved.

These advantages further suggest that the LPV could eliminate SARS-CoV-2 from the world.

Even if animal experiments and clinical trials all support the LPV strategy, this strategy should be widely discussed with public scrutiny before mass application.

Moreover, a comprehensive plan should be well designed and implemented. The plan should cover the following recommendations. First, as explained above, mass vaccination of the LPV should be conducted in hot seasons to reduce mixed infections. Second, mass vaccination of the LPV could initiate in the army, prisons, and countryside due to their good isolation facilities. Third, mass vaccination of the LPV should be conducted community by community, and simultaneously for the same community. All recipients should stay at home for certain days. If most people in the whole world could be vaccinated in a few months, the virus should have few people to sustain its circulation worldwide. In this sense, global collaboration is required to make enough vaccine for everyone. 39 The LPV vaccination could be mandatory to all people in order to build up adequate herd immunity against COVID-19. However, pregnant women and people with immunodeficiency or other illness should be excluded. These excluded people should be isolated for weeks to prevent infection caused by the virus from LPV recipients. This does not mean that the LPV increases the infection risk in these people because they otherwise shall catch the pandemic virus sooner or later.

Additionally, if the herd immunity of a community, city, or region is established and so the coronavirus cannot circulate, pregnant women and people with illness could be protected thereby.

Because feces of the vaccine recipients likely contain the virus, feces should be well managed at least for certain days. Moreover, domestic animals including cats and dogs should be isolated for certain days during the vaccination period. Similarly, this does not mean that the LPV increases the infection risk in domestic animals because they otherwise also have possibilities to contact the pandemic virus.

The whole world has entered a terrible crisis due to the pandemic of COVID-19. The LPV strategy could be a fast way out of the crisis, as supported by its successful application in the control of human and animal diseases. Five mechanisms could be This article is protected by copyright. All rights reserved.

employed to guarantee the safety of the LPV strategy which could reduce dramatically the morbidity and mortality. Collectively, the LPV strategy deserves global collaboration and financial support to conduct the relevant animal experiments and clinical trials, which themselves are highly valuable in science and for treatment of COVID-19 patients. Even if the LPV strategy is supported by the animal experiments and clinical trials, it should be implemented with cautiousness.

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We thank Meng Yang for her helpful advice and assistance.

The authors declare there are no conflict of interests.

JwC and JmC designed and wrote this article, and JmC made the major conclusions.

The data supporting the views of this article are available from the corresponding author on request.

The article does not contain the participation of animals and humans other than the authors.