key: cord-0989327-e9nf4z52
authors: Malave Sanchez, Melanie; Saleeb, Paul; Kottilil, Shyam; Mathur, Poonam
title: Oral Polio Vaccine to Protect Against COVID-19: Out of the Box Strategies?
date: 2021-07-09
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab367
sha: 1e55bc88db328693c069463c7e488455b9a62870
doc_id: 989327
cord_uid: e9nf4z52

The global coronavirus disease 2019 pandemic has raised significant concerns of developing rapid, broad strategies to protect the vulnerable population and prevent morbidity and mortality. However, even with an aggressive approach, controlling the pandemic has been challenging, with concerns of emerging variants that likely escape vaccines, nonadherence of social distancing/preventive measures by the public, and challenges in rapid implementation of a global vaccination program that involves mass production, distribution, and execution. In this review, we revisit the utilization of attenuated vaccinations, such as the oral polio vaccine, which are safe, easy to administer, and likely provide cross-protection against respiratory pathogens. We discuss the rationale and data supporting its use and detail description of available vaccines that could be repurposed for curtailing the pandemic.

The global coronavirus disease 2019 (COVID- 19) pandemic has forced the medical community to explore every possible solution to slow transmission, with the hope that lives will eventually return to normal. There are growing concerns from a public health perspective given ongoing challenges regarding vaccine equity, production, and distribution. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants also threaten to be more transmissible and escape from vaccine-acquired immunity complicated by continued noncompliance with social distancing and disparities among infection control and mitigation strategies between states.

While public health measures, including vaccination against COVID-19, are in full force, alternative therapeutics and methods of protection against infection are being studied and developed. One underexplored option to combat COVID-19 is a safe and available method that has been discussed in the medical literature since at least the 1950s: exploiting the nonspecific effects of live vaccines to combat other infections. Such use has been suggested for the oral polio vaccine (OPV) due to decades' worth of experience and proven efficacy.

OPV was first introduced in 1961 and was in the trivalent form, containing a mixture of the 3 live, attenuated poliovirus serotypes (1, 2, 3) [1] . Monovalent forms of the vaccine (containing serotypes 1 or 3) and the bivalent formulation (containing serotypes 1 and 3) are those most commonly used in vaccination campaigns. Of the 3 wild types of the poliovirus, types 2 and 3 were declared eradicated in 2015 and 2019, respectively, per the World Health Organization (WHO). There is currently a global campaign to withdraw the use of OPV and switch to inactivated polio vaccine (IPV) for vaccination campaigns. However, the potential benefits of OPV as an agent to prime the immune system and confer protection against other infections warrant a reexamination of this strategy.

In the 1950s, Voroshilova proposed that nonpathogenic enteroviruses were useful in the eradication of pathogenic enteroviruses. This finding was supported by the observation that the immunogenic effects of OPV were attenuated by the nonpoliomyelitis enteroviruses that colonized the gastrointestinal (GI) tract [2] . Subsequent studies have explored the effects of live enterovirus vaccines (LEVs) on generating nonspecific immune responses, including an increase of endogenous interferon inducers, T-cell lymphocytes, and overall cellular immunity. In Moscow and Kharkov, large epidemiologic surveys were performed with 6131 children that demonstrated LEV-4 and LEV-7 nonreactogenicity and vaccine safety [2] . The proven safety of LEVs prompted the Vaccine and Sera Committee of the USSR Ministry of Health to permit studies assessing the potential prevention of influenza and acute respiratory disease of up to 320 000 participants with the use of LEVs during the 1960s. Some of these studies demonstrated that LEV 4 and LEV 7 decreased cytopathic agents in the GI tract 4-fold from 29.3% to 7.7% after vaccination [2] . Incidentally, there was also an associated decrease in isolated infections from influenza, parainfluenza, respiratory syncytial virus (RSV), adenovirus, and herpesviruses [2] . Additional controlled trials conducted in the former USSR during the influenza seasons of 1968-1971 demonstrated a decreased incidence of influenza and acute respiratory infections (ARIs) in individuals who had received OPV 1-3 and LEV 4, 7 [3] [4] [5] . Chumakov et al. (1992) analyzed the results of these controlled trials and found that 60 065 (69.8%) individuals who received the oral Sabin type 1 and 2 vaccines had an average 3.8-fold decrease in acute respiratory infections when compared with 25 924 (30.1%) individuals who were unvaccinated [6] . They also observed that the decrease in incidence of influenza and other respiratory infections was significantly higher in oral Sabin vaccine recipients than influenza vaccine recipients (an analysis for P value was not made) [6] . LEV 4, 7 decreased the incidence rate of ARI by 2.6-fold, an effect similar to that of influenza vaccines. These findings led to the hypothesis that LEV and OPV may offer protection against other viral infections.

Recent studies have added to the growing evidence that vaccines may offer nonspecific protection against infections. A randomized controlled trial done in Guinea-Bissau looked at the effect of OPV at birth (OPV0) on infant mortality [7] . They enrolled 7012 neonates, of whom 3495 were randomized to the Bacillus Calmette-Guérin (BCG) group (intervention) and 3517 to the BCG and OPV0 group (standard of care). At 1-year follow-up, there were 87 deaths in the BCG arm and 73 in the BCG + OPV0 arm (overall hazard ratio [HR], 0.83). Irrespective of gender, BCG + OPV0 was associated with lower mortality compared with BCG alone [7] . In addition, no incident polio cases were identified during this trial period, indicating that the nonspecific effects of the vaccine could not be explained by decreasing polio cases. Andersen et al. (2020) analyzed 17 national OPV campaigns and examined mortality rates in children between 1 day and 3 years of age. Mortality was lower after OPV-only campaigns, with an adjusted mortality rate ratio (MRR) of 0.75 (95% CI, 0.67-0.85) [8] . Additional OPV campaigns reduced mortality further by 14% [8] .

In 2015, Sorup et al. conducted a retrospective cohort study in Denmark and investigated the admission rate of children due to infectious diseases depending on whether the most recent vaccine they had received was OPV, DTap-IPV-Hib (diphtheriatetanus-acellular pertussis-inactivated polio virus-Haemophilus influenzae type b), or MMR (measles, mumps, rubella). They found that when OPV was the most recent vaccine, there was a lower rate of admission for all type of infections-mostly lower respiratory tract infections-when compared with DTaP-IPV-Hib as the most recent vaccine [9] . They also observed that admission rates were lower when MMR was the most recent vaccine when compared with DTaP-IPV-Hib, but there was no statistical difference between OPV and MMR when either was given most recently. A similar study was performed in the United States using the MarketScan US Commercial claims database to evaluate the risk of hospital admission due to nontargeted infections (NTIs) in 311 663 children aged 16-24 months, depending on the last vaccine administered [10] . The study found that the risk of hospitalization from nontargeted infections was reduced in those who received a live vaccine vs an inactivated vaccine alone (HR, 0.50; 95% CI, 0.43-0.57). Similar to the findings by Sorup et al., the biggest reduction in NTIs was for lower and upper respiratory tract infections when using live vaccines. In children who received concomitant live and inactivated vaccines, the reduction in NTIs was less significant (HR, 0.78; 95% CI, 0.67-0.91); therefore, the investigators concluded that concomitant use of live and inactivated vaccines may have a "diluted" effect compared with live vaccines, but the effect is still present [10] . Mechanisms by which live and attenuated vaccines protect against NTIs have yet to be fully understood and are discussed below. The evidence thus far indicates that live vaccines present nontargeted benefits against other infectious diseases, improving overall mortality.

Other live vaccines have also demonstrated mortality benefit. The WHO performed a systematic review and found that BCG had a mortality benefit in children vaccinated at different ages [11, 12] . The effect was lower if the child had been vaccinated at an older age [11] . Investigators in Guinea-Bissau found a reduction in mortality in infants who had a scar after BCG vaccination, attributed to BCG vaccine-nonspecific protection [13, 14] . Prentice et al. (2021) performed an investigator-blind randomized controlled trial with 560 participants who were assigned to BCG at birth (n = 280) or at age 6 weeks (n = 280). They found that BCG vaccination at birth protected the participants against nontuberculous infectious diseases during the neonatal period [15] . The measles vaccine has also demonstrated a mortality benefit unexplained by preventing measles infection alone [11] and a higher mortality benefit in girls [11, [16] [17] [18] [19] . Aaby et al. (2010) performed a randomized controlled trial to evaluate if a 25% difference in mortality existed between children aged 4.5 months and 3 years of age after vaccination with the Edmonston-Zagreb measles vaccine at 4.5 months and 9 months, compared with the standard in Guinea-Bissau of 1 dose at 9 months of age. They randomized 6648 children after their 3 doses of diphtheria, tetanus, pertussis vaccine into 3 groups: Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), Edmonston-Zagreb measles vaccine at 9 months of age only (group B), and Schwarz measles vaccine at 9 months of age only (group C) [17] . They found that a 2-dose measles vaccination was associated with a 22% reduction in allcause mortality. They confirmed that prevention of measles infection only explained a small portion of the effect on overall mortality [17] . The nonspecific protective effects may exist in all live vaccines, but this requires further research (Table 1 ). [19] [20] [21] [22] . Live vaccines can then confer immunity by activating immune effector cells, which neutralize viral replication, promote opsonophagocytosis of pathogens, activate the complement cascade, bind to active sites of toxins [21] , or kill cells via direct contact or cytokine production. CD4 + T lymphocytes, activated by dendritic cells in response to vaccines, differentiate into T-helper subsets that have unique functions: T-helper (Th) 1 cells produce interferon (IFN)-γ, tumor necrosis factor (TNF), and interleukin (IL)-2 and protect against intracellular pathogens; Th17 effector cells protect mucosal surfaces and produce IL-17, IL-22, and IL-26; and Th2 cells mediate production of immunoglobulin (Ig) E via IL-4, IL-5, and IL-13 to protect against extracellular pathogens [21] . While antibodies produced from vaccination help prevent disease, the immune training by live vaccines is thought to decrease the severity of disease and the amount of damage to organic tissue, including mucosal surfaces, by reducing viral shedding and invasive pathogens, allowing for nonspecific protection against other pathogens. This effect was demonstrated by Upfill-Brown et al. (2017), a randomized controlled trial that found that OPV use was associated with decreased prevalence of Shigella and E. coli diarrhea among male children and of Campylobacter jejuni diarrhea among children of both sexes in Bangladesh [23] . In addition to promoting adaptive immunity, live vaccines provoke a reconfiguration of the innate immune cells by epigenetic manipulation of these cells, as seen with the BCG vaccine. Kleinnijenhuis et al. (2012) demonstrated that monocytic phenotype modification occurred at least 2 weeks after BCG vaccination in humans. The CD14+ monocyte population markedly increased after vaccination, with a positive associated change in CD11b and TLR 4 expression that was still present at 3 months postvaccination, mediated by PRR NOD2 by methylation of histone H3 at lysine 4 [20] . This led to a 2-fold increase in release of cytokines in response to nontargeted bacterial and fungal pathogens and an early enhanced antimicrobial capacity by the innate immune system [20] . Brook et al. (2020) demonstrated that BCG vaccination in neonatal mice was associated with marked improval in survival during sepsis by utilizing emergency granulopoiesis as a potential protective mechanism [24] . Its mechanism is thought to be due to an increase in hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-1β, and interleukin-3, -6, within a few hours after BCG vaccination [24] . Kavanagh et al. (2010) examined the effects of the attenuated pertussis vaccine BPZE1 on severity of pertussis infection in animal models. They found that attenuated BPZE1 was associated with reduced bronchial hyperreactivity and inflammatory infiltration of the airways compared with mice who were not immunized and challenged with a virulent pertussis strain [16] . BPZE1 reduced ovalbumin-induced IgE and increased IFN-gamma, suggesting predominant induction of Th1 rather than Th2 cells. Cauchi and Locht et al. (2018) proposed that BPZE1 offered heterologous protection against other respiratory pathogens, including influenza and RSV, by cross-reactive B and T cells. BPZE1 was associated with decreased death and lung colonization by B. bronchiseptica and reduced inflammation, neutrophil, and tissue damage in the lungs of mice. More importantly, BPZE1 protected against lymphocyte depletion and cytokine hyper-response, evidenced by decreased levels of IL-1β, IL-6, and granulocyte-macrophage colony-stimulating factor [18] . This effect may be mediated by the adenylate cyclase toxin (ACT) in PTX-deficient strains (a virulent factor important for transmission), inhibiting the expression of genes coding for proinflammatory cytokines IL-1β, TNF-α, and IL-8, hence opposing inflammatory responses [18] . These mechanisms may be the foundation of possible benefits against SARS-CoV-2, some examples of which are illustrated in Figures 1 and 2 and Table 2 . A summary of the evidence of the non-specific effects of vaccines can be found in Table 3 .

SARS-CoV-2 is a complex virus that has mechanisms of invasion and evasion of the immune system we have yet to fully understand. It seems to provoke a dysregulated, hyper-immune response leading to severe disease. Arunachalam et al. (2020) proposed that COVID-19 infection impairs the innate immune cells in the peripheral blood by suppressing cytokine production through suppressed TLR stimulation [25] . In addition, SARS-CoV-2 has a N-terminal nonstructural protein 1, which suppresses host gene expression and shuts down parts of the innate immune system involved in antiviral defense, such as IFN-β [26] . Earlier studies of SARS-CoV showed that its papain-like protease inhibits the IRF3 pathway, eliciting a high IFN response as well as inhibiting pro-inflammatory cytokines in TLR3 and retinoic acid-inducible gene pathways (RIG-1) [26, 27] . It also antagonizes the signaling activity of TLR7 for production of interferon, IL-6, and IL-8 [27] . Qian Zhang et al. (2020) found that 3.5% of patients with severe COVID-19 pneumonia had defects at 8 of 13 loci involved in the TLR3 and IRF7 induction of type 1 IFNs, further arguing the importance of such pathways [28] . Therefore, SARS-CoV-2 causes a maladaptive innate immune system response that also affects adaptive immunity [29] . If an impairment of the innate immune system is critical to SARS-CoV-2's transmission and infection, one may hypothesize that priming the innate immune system before infection can offset infectivity or attenuate COVID-19 disease.

TLR3/TLR7 stimulation is implicated in the nonspecific effect of vaccines by changing cytokine profiles and favoring Th1 rather than Th2 production, which plays a more significant role in response to viral infections [19] . In theory, this stimulation would provoke early activation of the innate immune system, including dendritic cells, which are the main determinants of CD4 T+ cell differentiation [16] . A skewed differentiation toward Th1 cells can lead to higher activation of CD8 T+ cells, extrafollicular B-cell help, enhanced dendritic cell activation, and rapid effector memory T-cell responses in the periphery to assist in cytotoxic activity against viruses [21] . In addition, the production of IFN-gamma may be beneficial, as it has been known to antagonize fibrosis and tissue remodeling by Th2 in asthma cases, which may help in reducing pulmonary disease in severe COVID-19 disease [16] . "Lifelong" immunity from these vaccines may be conferred by high antibody responses due to antigen persistence, which could lead to production of enough mucosal IgG and IgA to protect mucosal surfaces against viral invasion, ultimately protecting [21] against parenchymal damage by viruses or secondary pathogens [30] .

Benn et al. (2020) presented 6 principles of the vaccine paradigm based on assumptions and contradictions regarding the nonspecific effects of vaccines that might be useful in optimizing the use of such vaccines [31] . Principles such as "the most recent vaccination has the strongest nonspecific effects" lead us to hypothesize that even though SARS-CoV-2 suppresses TLR signaling, use of OPV or other live vaccines prophylactically before COVID infection could activate innate immunity via TLRs and prime the immune system for adaptive immunity in the case of subsequent infection with SARS-CoV-2. Though there is an effort by the WHO and UNICEF to withdraw OPV a year after wild polio virus eradication, the potential benefits of OPV regarding COVID-19 warrant prospective studies to assess the impact that OPV may have on decreasing the morbidity and mortality from COVID-19 worldwide. Given the high rates of morbidity and mortality from COVID-19 we have already experienced, it is vital to perform these studies immediately. Adverse effects associated with OPV exist; vaccine-associated paralytic poliomyelitis (VAPP) is a serious side effect more often associated with serotype 2 in unvaccinated people. VAPP is rare, occurring every 1 in 2.7 million doses of OPV [32] , and there is no evidence suggesting that VAPP causes outbreaks [1] . Circulating vaccine-derived poliovirus (cVDPV) is associated with person-to-person transmission that circulates in a community, but it is also considered rare. From July 2019 to February 2019, 33 outbreaks were reported, with 366 cases identified in 2019 [33, 34] . In 2020, there was an increase of 1037 cases of cVDPV reported; these were attributed to poorquality response to outbreaks, declining immunity to the type 2 virus after switching from trivalent to bivalent OPV, and poor routine immunization [34] . This was further exacerbated by a 4-month pause in house-to-house polio vaccination campaigns [34] . The major risk factor for cVDPV is low vaccination and low immunity in a community. Outbreaks can be prevented and stopped with high-quality, effective, largescale immunization events. Furthermore, under the WHO Emergency Use Listing, the vaccine nOPV2 will initiate use in countries where cVDPV2 is causing outbreaks, with the end goal of stopping cVDPV2 [34] . However, transmission of infection via shedding after vaccination is less likely in highincome countries such as the United States, where people are vaccinated at a young age and considered to have lifelong immunity to polio virus.

The dysregulated immune response in COVID-19 disease is critical in the morbidity and mortality associated with SARS-CoV-2 infection, leading to massive tissue and endothelial damage. "Trained" immunity by live, attenuated vaccines may be a method to prophylactically prevent infection and/or progression of disease by inducing a robust response by the innate immune system, which not only would confer protection against the evasive mechanisms of SARS-CoV-2, but also prime adaptive immunity. This review presents the available evidence for the nonspecific effect of vaccines and proposed mechanisms by which these vaccines may mitigate the severity of COVID-19 disease and likely future pandemics due to respiratory viruses. The low-cost, safety, and proven nonspecific effects of OPV make it an excellent candidate for immediate use while battling SARS-CoV-2 vaccine inequity, distribution, and ongoing infection. [23] • Reduction in detection of C. jejuni/coli in all infants [23] • Lower admissions due to lower respiratory tract infections in vaccinated children [9] • OPV campaigns associated with significant decreases in mortality rate (MRR, 0.75), with additional doses associated with a reduction of 14% in mortality rate [8] MMR • Lower admissions due to lower respiratory tract infections in vaccinated children [9] • A risk reduction of up to 35% in hospitalization due to infectious diseases in the second year of life in high-income countries [54] BCG • Reduction in mortality of 3-fold in neonatal vaccinated boys [55] • BCG scar associated with lower mortality for children when compared with those without a scar (MR, 0.45; 95% CI, 0.21-0.96) [56] • BCG scar associated with a significant reduction in risk of death from malaria [56] • An increase of 10% in BCG index was associated with a mortality reduction of 10.4% in COVID-19 mortality [57] • Induces emergency granulopoiesis improving survival in neonatal mice during sepsis [24] Influenza • Produces strong innate immune responses to provide indirect protection against RSV [19] Monovalent measles • Two doses were associated with an all-cause mortality reduction of 22% when given before DTP vaccine in children 4.5-36 months of age [17] • Lower mortality among vaccinated children vs unvaccinated children (HR, 0.76; 95% CI, 0.63-0.91), especially for early vaccinated children [58] • Early vaccination was associated with a lower risk of hospital admission, particularly for respiratory infections [59] Attenuated Bordetella pertussis vaccine (BPZE1) • In animal studies, protects against inflammation and allergen-driven airway pathology from infections due to Bortedella species, RSV, and influenza [16, 18] Abbreviations 

Centers for Disease Control and Prevention. Polio disease and poliovirus

Potential use of nonpathogenic enteroviruses for control of human disease

Enterovirus Infections of Man

Acute respiratory diseases

Use of live enterovirus vaccines for urgent prophylaxis of influenza

Live enteroviral vaccines for the emergency nonspecific prevention of mass respiratory diseases during fall-winter epidemics of influenza and acute respiratory diseases

The effect of oral polio vaccine at birth on infant mortality: a randomized trial

National immunization campaigns with oral polio vaccine may reduce all-cause mortality: an analysis of 13 years of demographic surveillance data from an urban African area

Oral polio vaccination and hospital admissions with non-polio infections in Denmark: nationwide retrospective cohort study

Risk of nontargeted infectious disease hospitalizations among US children following inactivated and live vaccines

Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review

Systematic review of the non-specific effects of BCG, DTP and measles containing vaccines

BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG?

BCG scarring and improved child survival: a combined analysis of studies of BCG scarring

Delayed BCG Study Team. BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial

Attenuated Bordetella pertussis vaccine strain BPZE1 modulates allergen-induced immunity and prevents allergic pulmonary pathology in a murine model

Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial

Non-specific effects of live attenuated pertussis vaccine against heterologous infectious and inflammatory diseases

Non-specific effect of vaccines: immediate protection against respiratory syncytial virus infection by a live attenuated influenza vaccine

Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes

2-Vaccine immunology

Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

Nonspecific effects of oral polio vaccine on diarrheal burden and etiology among Bangladeshi infants

BCG vaccination-induced emergency granulopoiesis provides rapid protection from neonatal sepsis

Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans

Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2

SARS coronavirus papain-like protease inhibits the TLR7 signaling pathway through removing Lys63-linked polyubiquitination of TRAF3 and TRAF6

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Innate immune signaling and proteolytic pathways in the resolution or exacerbation of SARS-CoV-2 in Covid-19: key therapeutic targets?

Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection

Global Polio Eradication Initiative: annual report 2015: eradication within reach

Update on vaccine-derived poliovirus outbreaks -worldwide

Global Polio Eradication Initiative. GPEI strategy for the response to

Vaccines for children program

Fundamentals of vaccine immunology

Vaccine excipient summaryexcipients included in U

Revaccination with measles-mumpsrubella vaccine and infectious disease morbidity: a Danish register-based cohort study

Mucosal IgA responses in healthy adult volunteers following intranasal spray delivery of a live attenuated measles vaccine

Food and Drug Administration. Measles, mups, rubella package insert

World Health Organization. OPV package insert

Worldwide cost-effectiveness of infant BCG vaccination

Revaccination with live attenuated vaccines confer additional beneficial nonspecific effects on overall survival: a review

Mucosal delivery of tuberculosis vaccines: a review of current approaches and challenges

Food and Drug Administration

Cultivation of mycobacterium bovis BCG in bioreactors

FluMist® quadrivalent package insert

Food and Drug Administration

Institute of Tropical and Infectious Diseases (UNITID) Group and the Kenyan AIDS Vaccine Initiative-Institute of Clinical Research (KAVI-ICR) Team. Live attenuated zoster vaccine boosts varicella zoster virus (VZV)-specific humoral responses systemically and at the cervicovaginal mucosa of Kenyan VZV-seropositive women

Cellular and humoral responses to a second dose of herpes zoster vaccine administered 10 years after the first dose among older adults

ZOSTAVAX® (zoster vaccine live) package insert

VARIVAX® (varicella virus vaccine live) package insert

Non-specific effects of MMR vaccines on infectious disease related hospitalizations during the second year of life in high-income countries: a systematic review and meta-analysis

Rapid protective effects of early BCG on neonatal mortality among low birth weight boys: observations from randomized trials

BCG vaccination scar associated with better childhood survival in Guinea-Bissau

BCG vaccine protection from severe coronavirus disease 2019 (COVID-19)

Is early measles vaccination associated with stronger survival benefits than later measles vaccination?

A randomized trial of a standard dose of Edmonston-Zagreb measles vaccine given at 4.5 months of age: effect on total hospital admissions