Can existing live vaccines prevent COVID-19?

Following an objective review of the scientific evidence and claims made by the authors in this opinion piece (and in the associated mass media coverage), colleagues and I systematically evaluated the health and economic impacts of reintroducing unlicensed OPV into the US in 2020 to respond to COVID-19. Risk Analysis published our peer-reviewed study on October 20, 2020 (open access, doi: 10.1111/risa.13614). Bottom line: Our study shows that reintroducing OPV into the US as proposed would come with substantial costs (estimated at over $4.4 billion to deliver one dose of OPV to all Americans, if the vaccine could even be procured) and potential health risks that far exceed any potential benefits in the fight against COVID-19. In our public health efforts to best manage the COVID-19 pandemic, we need to focus our investments on well-evaluated interventions for which the expected specific benefits exceed the expected costs and risks. Giving a non-specific vaccine could undermine later efforts to obtain high coverage of effective, COVID-19 specific vaccines.

While I support the authors' intention to test OPV as an innate immune system booster that could provide some protection against Coronavirus 19 I wonder if something is being missed. Young children seem to be spared Covid 19 infection. Could that be because they have been relatively recently immunized? If so, it would be with IPV since OPV has not been used in the US since 2000. Might it be the MMR that is conveying protection? Or perhaps a combination. It would seem to me to be a good idea to consider it in the mix.

The clinical outcomes of inhaled nitric oxide gas and BCG immunotherapy may offer insight as to coronavirus' vulnerability. Both approaches that are intended to restore pulmonary function and slow viral replication are likely working through the same molecule, nitric oxide.

Several medical device companies have received FDA's blessing for emergency expanded access to offer inhaled nitric oxide gas for treating Covid-19. During the 2003 SARS outbreak, inhalation of nitric oxide improved lung oxygenation and shortened the length of ventilatory support (1). Aside from improving lung function, nitric oxide also showed direct antiviral activity (2). Suggested druggable targets include nitric oxide interfering with the interaction between viral S-protein and its cognate host receptor, ACE-2, and nitric oxide-mediated S-nitrosylation of viral cysteine proteases, critical for virulence and replication (2,3).

Trials are also underway to test BCG's ability to rev-up the primitive or innate arm of the immune system with the hope to provide protection against SARS-CoV-2. BCG is a weakened, live bacterium, bacillus Calmette-Guérin that is a distant relative of the pathologic mycobacterium that cause leprosy and tuberculosis, TB. BCG has been administrated for decades to newborns in many countries as a vaccine against TB with wildly inconsistent outcomes. However, several countries have observed nearly a 50% reduction in mortality in children vaccinated with BCG, an effect that is too big to be explained by protection against TB alone (4). There is also suggestive evidence that countries with a BCG policy in place had slower growth of both cases and deaths resulting from Covid-19 as compared to countries that do not vaccinate with BCG.

Based on the capacity of BCG to reduce the incidence of respiratory tract infections in children, to exert antimicrobial effects against a diverse mix of intracellular pathogens including Leishmania major and Francisella tularensis in preclinical models and to reduce viremia in experimental human models of viral infection, BCG may prove to be equally effective as a prophylactic against Covid-19. In studies when evaluated for nitric oxide's role in non-specific immunity, it was found that BCG triggers cytokine-dependent, inducible-nitric oxide synthase expression resulting in antimicrobial levels of nitric oxide. Neutralization of IFN-γ and TNF-α with monoclonal antibodies to these cytokines blocked nitric oxide production and rendered BCG protected animals susceptible to lethal infection (5). Interestingly, anti-microbial inducible nitric oxide synthase is not limited to immunosurveillance cell such as the alveolar macrophage but can also be elicited in airway epithelial cells and fibroblasts among many other types of non-immune cells (5). Matter of fact, bladder cancer patients treated with BCG showed an upregulation of urothelial-associated nitric oxide synthase and an increase in cytotoxic levels of bladder nitric oxide production (6). BCG was the first FDA-approved immunotherapy to reduce the risk of bladder cancer recurrence by stimulating a non-specific immune response that targets bladder cancer cells. Today, approximately 70% of bladder cancer patients go into remission after BCG immunotherapy.

If nitric oxide emerges to be the linchpin in the BCG trials, such results, together with the inhalation studies, the outcome would offer meaningful insights as to re-designing prophylactic and therapeutic strategies to combat coronavirus going forward.

1. Chen L et al. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing. Clin Infect Dis. 2004. 15:1531-5.

2. Akerstrom S et al. Dual effect of nitric oxide on SARS-CoV replication: viral RNA production and palmitoylation of the S protein are affected. Virology. 2009. 395(1):1-9.

3. Saura M et al. An antiviral mechanism of nitric oxide: inhibition of a viral protease. Immunity. 1999. 10(1):21-8.

4. Arts RJW et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018. 23:89-100.

5. Green SJ et al. Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens. Immunol Lett. 1994. 43: 87-94.

6. Morcos E et al. Bacillus Calmette-Guerin induces long-term local formation of nitric oxide in the bladder via the induction of nitric oxide synthase activity in urothelial cells. J Urol. 2001 Feb;165(2):678-82.

The authors correctly assert that oral poliovirus vaccine (OPV) "could provide temporary protection against coronavirus disease 2019 (COVID-19)." Viral infection with a natural virus or a live virus vaccine can induce an interferon response and the anti-viral state in humans, but it is short-lived. If vaccination with OPV could be timed to occur a few days or weeks before a person was exposed to SARS-CoV-2, it may give some protection by inducing the antiviral state, and by providing 'bystander help' where cytokines produced in the OPV response can also then stimulate SARS-CoV-2 specific lymphocytes. However, a concern exists for bystander effects, which may be associated with autoimmune activation as well (1).
The authors discuss poliovirus infections in 1959 in Singapore where vaccination against PV2 protected against PV1 even though neutralizing antibodies to PV2 do not neutralize PV1. The authors conclude that "the most plausible explanation was viral interference, which presumably is mediated by innate immunity." However, the PV2 vaccine induced a myriad of antibodies that would cross react with PV1 (2-5) and provide some protection through opsonization, complement activation, and antibody dependent cell mediated cytotoxicity. PV1 and PV2 are the same genus and species, and the PV genome is approximately 7500 nucleotides, encoding thousands of peptides that can provide some cross protecting epitopes for anti-viral cytotoxic T lymphocytes and B lymphocytes producing antibodies.
Neutralization is just one aspect of immunity and is often over-emphasized in vaccine evaluation. In our trials of SARS vaccines in ferrets, the inactivated viral vaccine induced 15 times the amount of neutralizing antibodies as the Adenovirus vectored Spike and Nucleocapsid vaccine, but did not protect significantly better (6).
Similar interest in immune stimulation has been generated to the tuberculosis BCG vaccine, but a recent study also gives evidence that BCG vaccination is not protective against COVID-19 (7)
References 1. Christen Clin Exp Immunol 2019 2. Puligedda Vaccine 2017 3. Vrijsen JVirol 1984 4. Z Chen PNAS 2013 5. Z Chen JVirol 2011 6. See J GenVirol 2008 7. Asahara https://doi.org/10.1101/2020.04.17.20068601