key: cord-0910890-vycjyuh9 authors: Mosaddeghi, Pouria; Shahabinezhad, Farbod; Dorvash, Mohammadreza; Goodarzi, Mojtaba; Negahdaripour, Manica title: Harnessing the non-specific immunogenic effects of available vaccines to combat COVID-19 date: 2020-11-13 journal: Human vaccines & immunotherapeutics DOI: 10.1080/21645515.2020.1833577 sha: d7e1651a047f2acead975d744570dfecc5bd22cd doc_id: 910890 cord_uid: vycjyuh9 No proven remedy is identified for COVID-19 yet. SARS-CoV-2, the viral agent, is recognized by some endosomal and cytosolic receptors following cell entry, entailing innate and adaptive immunity stimulation, notably through interferon induction. Impairment in immunity activation in some patients, mostly elderlies, leads to high mortalities; thus, promoting immune responses may help. BCG vaccine is under investigation to prevent COVID-19 due to its non-specific effects on the immune system. However, other complementary immune-induction methods at early stages of the disease may be needed. Here, the potentially preventive immunologic effects of BCG and influenza vaccination are compared with the immune response defects caused by aging and COVID-19. BCG co-administration with interferon-α/-β, or influenza vaccine is suggested to overcome its shortcomings in interferon signaling against COVID-19. However, further studies are highly recommended to assess the outcomes of such interventions considering their probable adverse effects especially augmented innate immune responses and overproduction of proinflammatory mediators. The novel coronavirus disease 2019 (COVID-19) was announced as a pandemic by the World Health Organization (WHO) shortly after its first report in Dec. 2019 in Wuhan city, China. 1 While worldwide enormous efforts are ongoing to find preventive and/or therapeutic approaches for COVID-19, its huge burden on countries and societies 2 has prompted politicians to look for solutions as well. Donald Trump asked a while ago whether the flu vaccine combats the novel coronavirus, which was answered with a direct NO! Although this naïve question was raised because of a lack of knowledge about vaccination basics, it seems that the answer to his question could probably be yes! Recently, it was suggested that the booster BCG (Bacillus Calmette-Guérin) vaccine, could have beneficial effects on preventing COVID-19 infection 3 and reducing the incidence and severity of COVID-19 in previously BCG-vaccinated groups through its non-specific effects (NSEs). It was also proposed that the differences in COVID-19 severity amongst countries could be, to some extent, explained by various national policies on BCG children vaccination. 4, 5 However, this claim was questioned by some other studies. 6, 7 In this context, an open-label two-group phase III randomized controlled trial was first begun in up to 4170 healthcare workers in Australia. It is currently ongoing and aims to reveal the possible preventive effects of BCG vaccination against COVID-19. 8 Presently, one observational and seven interventional clinical trials are also being conducted on this subject, which are briefed in Table 1 . 9 The observed more efficient and improved immune responses against reinfections in the plants and invertebrate that lack adaptive immunity, and surprisingly in some mammals, encouraged researchers to investigate whether this process could also occur in humans. 10 Thus, several epidemiological studies and clinical trials were performed to explore the post-effects of vaccination with live-attenuated vaccines (LAVs), which mimic a natural infection. Though, the capability of LAVs in generating a sort of crossprotection against some other non-related pathogens was established in several studies. 11 In this regard, the NSEs of several vaccines (BCG, DTP, and measles vaccines) have been investigated. 12 One primary mechanism behind this phenomenon was found to be the induction of long-lasting epigenetic changes in the innate immune cells, a process called "trained immunity". 11 Besides, heterologous lymphocyte responses may partly account for some NSEs of vaccines. 13 On this point, antigen cross-reactivity and bystander activation of unrelated T and B cells are considered as possible mechanisms. The bystander lymphocytes could exert protective roles against unrelated heterologous pathogens through antigen-specific bystander responses or antigen-non-specific innate mechanisms, such as interferon (IFN)-γ production, which activates macrophages. 11, 13 The higher mortality rates in elderlies is a main concern in the COVID-19 pandemic, which is probably related to immunosenescence, or age-associated deterioration of immune functionality, 14 leading to suboptimal immune responses. In view of this, boosting the immune responses against SARS-CoV-2 could potentially reduce the disease incidence and severity in this population as well. Herein, a model on the immune responses against COVID-19 is proposed first. Then, the Yin and Yang of the NSEs of LAVs are described with a focus on BCG and influenza vaccines. Finally, the probable supportive roles of these vaccines on the protection against COVID-19 would be discussed. A brief overview of immune responses to SARS-CoV-2 is represented in Figure 1 . SARS-CoV-2, similar to SARS-CoV, enters the cells through angiotensin-converting enzyme II (ACE2) receptor. It also uses transmembrane protease serine 2 (TMPRSS2) receptor to prime its spike (S) protein in target cells. 15, 16 TMPRSS2 plays a role in influenza virus pathogenicity as well by cleaving hemagglutinin. 17 Other yet-unknown cellular entry modes might also be involved in SARS-CoV-2 infection, especially considering that only minimal percentages of leukocytes express ACE2. [18] [19] [20] Host cells possibly recognize SARS-CoV-2, same as other RNA viruses, first by endosomal pattern recognition receptors, such as Toll-like receptor (TLR)3 and TLR7, as well as cytosolic RNA receptors, such as retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein (MDA) 5. IFN-α or IFN-β (hereafter referred as IFN-I) and other proinflammatory mediators are induced following recognition of the virus, 21 playing a crucial role in controlling CoV infections. Type-I IFNs could enhance the function of immune cells, including antigen-presenting cells (APCs), natural killer (NK) cells, T cells, and B cells. 22, 23 Lung resident respiratory dendritic cells (DCs) seem to process the acquired viral particles or antigens from the SARS-CoV-2-infected cells, then present it to the naïve circulating T cells in draining lymph nodes. 21, 24 The activated T cells, migrate to the infection site and secrete effector cytokines such as IFN-γ, which directly inhibits viral infection. Th1 type immune response seems to play a crucial role in the effective control of SARS-CoV infection. Higher rates of mortality was detected in patients with more serum Th2 cytokines. 21 The exposure of naïve T cells to IFN-I, IFN-γ, and IL-12 is vital for Th1 cell polarization. 25 Since neutralizing antibodies (NAbs) limit the viral infections, delayed and weak antibody production was also associated with poor clinical outcome in SARS. 20 Moreover, the timing of IFN-I induction also seems crucial for the fine-tuning of B cell activation and consequent NAb production. 22 Coronaviruses can circumvent the immune responses, particularly IFN-mediated antiviral responses, and replicate to reach a high peak load. 26 Similar to SARS and MERS, substantial dysregulations of immunological responses occur in SARS-CoV-2 infection. 20 Significant T cell lymphopenia, in particular CD4 + T cells, an elevated exhaustion level of T cells with reduced functionality, lower percentages of monocytes, eosinophils, and basophils, as well as higher neutrophillymphocyte-ratio (NLR), were observed in COVID-19 patients in different studies. [27] [28] [29] The elevated levels of IL-1B, IFN-γ, IFN-γ-inducible protein 10 kDa (CXCL10; IP10), monocyte chemoattractant protein (MCP)1, as well as IL-4 and IL-10, which are related to Th1 and Th2 responses, respectively, were also identified. The enhanced proinflammatory cytokines, to some extent, could contribute to the increased infiltration and activation of leukocytes in the lungs and subsequent lethal pneumonia. 30, 31 Additionally, the elevated levels of IL-6 is considered as an early biomarker of the aggravation of COVID-19 clinical course, which is associated with cytokine storm. 32 Fu et al. 20 categorized SARS-CoV-2-mediated inflammatory responses into two different stages. The primary response, which occurs due to viral replication and consequently mounts the host antiviral responses and viral-induced ACE2 downregulation and shedding. The primary inflammatory response is almost tolerated by patients and has a protective role against the infection through viral load reduction or viral clearance. These possible mechanisms, in turn, cause elevated levels of proinflammatory cytokines/chemokine and cellular damage due to apoptosis and pyroptosis, 33 shaping the second stage of immune responses. This stage is initiated with the generation of adaptive immunity and NAb secretion. 23 The produced a. Optimal innate and adaptive immunity responses: The virus binds to ACE2 to infect cells. The engagement of pattern recognition receptors (PRRs) results in the production of interferons I and other proinflammatory mediators, which induces dendritic cells (DCs) to process antigens and present them to naïve circulating T cells, leading to T cell activation. The activated T cells migrate to the site of infection and secrete effector cytokines, such as IFN-γ. The APCs also induce B cells leading to optimal NAb production. b. Early and sub-optimal NAb activity results in antibody-dependent enhancement, leading macrophages to be exploited for virus replication. This process also causes elevated cytokine production and subsequent immunopathological overreactions. APC: Antigen Presenting Cell, NAb: Neutralizing Antibody NAbs could trigger Fc receptor-mediated antibody-dependent enhancement (ADE) (Figure 1b) , which possibly occurs due to early and sub-optimal antibody activity. This process could cause persistent viral replication, skewing of the macrophage responses, and further exuberant inflammatory responses, and subsequent cellular damage and lung injury. 31 Noteworthy, the possible role of ADE in COVID-19 severity was also suggested by other researchers recently. 32 Besides, given the crucial role of T cells, in particular CD4 + and CD8 + T cells, in modulating the over-activated inflammatory responses, some studies suggested that suboptimal and decreased T cell numbers generated by SARS-CoV-2 infection may also result in weak cellular immunity and undesired inflammatory responses. 27,34 The relative timing of the IFN-I response and maximal viral replication was shown to contribute to the disease severity in SARS and MERS. 30, 35 Notably, IFN therapy before the virus titer peak decreased inflammatory cytokines production and generated protective roles in MERS-CoV infected mice. In contrast, at the later stages of the disease (two or 4-days post-infection), enhanced proinflammatory cytokines, increased infiltration, and the higher total number of highly activated monocytes, macrophages, and neutrophils may result in fatal pneumonia. 35 The key role of dysregulated IFN-mediated immune responses in SARS-CoV-2 infection was uncovered as well. Despite heavier virus replication than SARS-CoV, SARS-CoV -2 does not significantly induce type-I, -II, or -III IFNs. 36 Consistent with this finding, it was revealed that IFN-I deficiency could be considered as a hallmark of severe COVID-19. 37, 38 Moreover, impaired IFN-mediated immune responses, with a reduced dynamic range, in response to direct pattern recognition receptor (PRR) stimulation and viral infection were uncovered in older individuals. 39 The impaired IFN antiviral responses could, to some extent, explain the poor clinical outcomes in elderlies. 32 In congruence with these studies, Hadjadj et.al suggested that IFN administration could be used to overcome the IFN-I deficiency issue. On the other hand, applying anti-inflammatory agents that target IL-6 or TNFα, could, to some extent, dampen the inflammation and subsequent immunopathogenic over-reactions. 38 As mentioned before, using LAVs might help in reducing the risks of other infections through NSEs. 11 In the following, the possible heterologous effects of BCG and influenza vaccines will be discussed. The impact of BCG, influenza vaccine, and IFN-I on the immune system in comparison with the immunity dysregulation caused by COVID-19 or aging are presented in Table 2 . BCG vaccine is a LAV used in many countries early after birth against tuberculosis (TB) disease. It has been injected to over four billion people so far. 66 BCG vaccination is also recommended to reduce the mortalities of pandemics. 67 Numerous studies have indicated the non-specific protective effects of BCG vaccination against viral infections caused by both RNA and DNA viruses. For instance, BCG vaccination could reduce the risk of respiratory tract infections in elderlies and adolescents and substantially enhance the responsiveness to influenza A and hepatitis B vaccines. 67 The heterologous effects of BCG vaccination against viral infections may be exerted through several mechanisms. One fundamental mechanism is trained immunity induction. BCG vaccination could stimulate immunological memory in NK cells, monocytes, and macrophages. 46, 68 It also led to enhanced IFN-γ and monocyte-derived cytokines 'four-to seven-fold' and 'two-fold', respectively, in healthy volunteers. 69 The importance of rapid and robust innate immune responses, as the primary SARS-CoV-2-mediated inflammatory response, in reducing viral load or even viral clearance is well-established. 20 However, the raised production of proinflammatory cytokines after BCG vaccination and subsequent cellular damage due to apoptosis or proptosis should be considered. 20, 33 On the other hand, BCG vaccination could also induce nonspecific lymphocyte responses through both cross-reactivity and bystander activation. 11, 13 For instance, BCG vaccination prior to pathogen insult or vaccination boosted the antibodymediated responses. 46 Moreover, it could enhance the responsiveness of Th1 to non-specific secondary infections as well as Th17 corresponding cytokine induction, such as IFN-γ, up to 1 year. 46 The beneficial impacts of BCG vaccine on adaptive immunity could reasonably dampen the secondary inflammatory responses to SARS-CoV-2 and the consequent multi-organ failure. 13, 70 While there are multiple publications on BCG-induced NSEs for viral infections, there is a concern for its use in COVID-19 prophylaxis; as it induces the suppressor of cytokine signaling 1 (SOCS1), a crucial negative regulator in the JAK-STAT signaling pathway, 54 which can lead to IFN signaling suppression. To minimize this obstacle, Mizuno et al. 54 demonstrated that the administration of SOCS1 antagonistexpressing recombinant BCG enhanced the immune responses in a mouse model. Interestingly, BCG plus IFN-α, as a vaccine adjuvant, 71 could promote Th1 type cytokines secretion and consequent effective immune responses. 72 Moreover, it has been revealed that pretreatment of DCs with IFN-β results in the production of larger amount of IL-12p70 and IL-12, which could improve DC function and causes consequent enhancement in Th1 responses. The authors conclude that IFN-β could be used as an adjuvant and enhance the BCG immunogenicity. 73, 74 Another study revealed that the treatment of cells with IFN-β or IFN-γ created epigenetic memory resulting in faster and higher IFN-stimulated gene (ISG) induction after re-stimulation. 75 Therefore, the administration of BCG plus IFN might rationally antagonize the adverse regulatory effects of SOCS1 and augment BCG-induced antiviral immune responses to some extent. However, BCG vaccine-related pulmonary complications, such as hypersensitivity reactions and mycobacterial pneumonia, have to be considered. 76 Thus, cautious studies should be Table 2 . The impact of BCG, influenza vaccine, and interferon (IFN)-I on the immune system compared with the dysregulation of immunity as a result of COVID-19 or aging. Influenza vaccines IFN-I Aging COVID-19 PRRs Engaging TLR2, TLR4, TLR8, and C-type lectin receptors, 40 NOD-like receptors, RIG-I 41 Engaging TLR7, 42 LAIV: increasing expression of RIG-I and TLR-3 Significant T cell lymphopenia, 28, 65 elevated exhaustion of T cells and reduced functionality, 29 increased in the mortality rate of patients with more serum Th2 cytokines [17] (Continued) performed to investigate the potential synergistic effects and safety profile of the proposed approach. Different types of influenza vaccines, including live-attenuated influenza vaccine (LAIVs) and inactivated influenza vaccines (IIVs), are marketed containing the antigens from certain viral strains. Some formulations also include adjuvants. 77 Such diverse constituents cause variety in cytokine induction capabilities of influenza vaccines. 78 For instance, TIV (trivalent subunit inactivated influenza vaccine) showed a stronger early induction of type-I and -III IFNs and higher amounts of activated DCs and proinflammatory cytokines, such as TNF, IL-6, −10, and −1β, than LAIV in an in vitro research on unadjuvanted influenza vaccines. Moreover, TIVs have shown some adverse events in children. 79 On the other hand, LAIVs were found to protect against respiratory infections 80 and induce innate immunity through various methods, 56 while also triggering a broader spectrum of immunity against different serotypes of influenza virus than TIVs. 81 Both TIV and LAIV induced the expression of IFN genes, which was observed on day one and seven after vaccination for TIV and LAIV, respectively. 55 It was suggested that the trained immunity induced by influenza vaccine is, to some extent, related to induction of the pro-inflammatory mediators and IFN production. 62, 80 It is hypothesized that a respiratory virus infection confers immunity against the same and other respiratory viruses for a short time, perhaps a few weeks. Such protection is because of activation of the innate immune response mediated by the release of IFN-I and other cytokines that have broad protective effects against a range of viruses. This phenomenon is called viral interference. 82 To inspect this concept, the short-term non-specific protection of coldadapted, live attenuated influenza vaccine (CAIV) against subsequent RSV infection was investigated in a mouse infection model 80 The author hypothesized that since influenza vaccine and RSV share common features in term of pathogenesis, influenza vaccine could attenuate the severity of RSV infection. Noteworthy, the protective effects of influenza vaccine were significantly diminished in TLR3-/-TLR7 -/-mice, which suggests the importance of TLR3/7 signaling pathways in the beneficial protective effects of influenza vaccine. The author proposed that the heterologous effects of influenza vaccine against MERS infection need further investigations. 80 An epidemiological article also validated this effect on RSV infection. 82 The immune responses to CoV and influenza infections seem comparable as they share some common features, including stimulation of TLRs and RIG-I as well as subsequent antiviral-mediated immune responses. 21 Therefore, the potential role of influenza vaccine in generating a non-specific, short term antiviral effect against SARS-CoV-2 has been suggested. 80 In this regard, a few recent reports have displayed a hypothetical beneficial role of influenza vaccines against COVID-19 infection in high-risk groups. 81,83 While Salem et al. described a flu-induced bystander effect of the generated immune responses as a probable protective mechanism, Kiseleva et al. opined that the LAIV might be more suitable than IIV because of its broad-spectrum potency. On the other hand, there are concerns about the dampening effect of influenza vaccines on the immune responses to SARS-CoV-2, as well. Because influenza infection can result in TLR desensitization for several months, suppressing one of the main defense mechanisms of the innate immunity against COVID-19. 84 Furthermore, influenza disease has shown some bizarre phenomena such as "vaccine-associated viral interference", which implies that a viral infection would generate a nonspecific short-time protection against other viruses normally, 85 which could be impeded when a vaccine is administered. 86 Another concern is "original antigenic sin" phenomenon, which denotes that in encountering with a similar or close pathogen, the immune system may fail to develop an effective immune response against the newer pathogen and would depend on the memory of the previous pathogen. 87 Therefore, a successful vaccination should include all the subtypes of a pathogen. 88 This phenomenon is highly important in vaccine design, expressing the importance of extensive clinical trials to validate the safety and side effects of vaccines. 89 However, original antigenic sin has been rarely reported in a cross-disease manner and is mostly important for expected mutations in the same pathogen family. A similar phenomenon is "heterosubtypic non-specific temporary immunity", in which the previous infection with a pathogen temporarily reduces the risk of future infections with another subtype. The phenomenon has been observed for influenza in the unvaccinated populations who had previous seasonal influenza infections and were less susceptible to get infected with pandemic influenza A (H1N1) 2009. 90, 91 It is also rarely observed among different families of pathogens. 92, 93 However, a substantial negative association between influenza vaccination and higher COVID-19 incidence or other infections has not been reported. 94, 95 All in all, the positive and negative sides of the influenza vaccines should be further investigated to evaluate their impact on COVID-19. On the other hand, BCG vaccination has been suggested as an adjuvant for influenza vaccination to increase its efficacy, especially in elderlies. 96 It could be conferred from Table 2 that influenza vaccine could effectively induce IFN mediated immune responses. Hence, the co-administration of BCG and influenza vaccine might harness the beneficial heterologous effects of these vaccines and be a potentially effective approach to combat COVID-19. However, it needs to be validated through experiments. Given the role of immune system overreactions in COVID-19induced cytokine storm and the resultant serious harm to body organs and even death, the interventions that could reverse such hyperactivated immunological responses could be of high value. In this regard, LAVs, especially BCG vaccine, could hinder viral replication and the subsequent pathological inflammatory responses in COVID-19 via the arousal of innate and adaptive immunity, especially in the aged and immunocompromised groups. However, the probable adverse effects of BCG vaccination should be considered, including the induction of SOCS1 expression, which may cause the suppression of IFN signaling. In view of the importance of IFN signaling pathway in reducing viral replication early after the infection, the use of a SOCSI-antagonist expressing recombinant BCG or a combination of BCG vaccine with IFN-I might help to partly reverse this detrimental effect and boost the immune system successfully against SARS-CoV-2. These approaches deserve more investigation and experience to be validated in respect to protocol efficacy and safety. The co-administration of BCG and influenza vaccine might also be potentially a candidate approach to combat COVID-19 and could probably exploit the positive impacts of these vaccines. However, the probability of undesired immunopathological overreactions and cumulative immune aberrations generated by the two vaccines should be taken seriously. In this respect, the risk of augmented innate immune responses, in particular, overproduction of proinflammatory mediators and overstimulation of immune responses, should also be regarded. In a nutshell, if any vaccine is to be used to support against COVID-19, while compensation for the virus-induced attenuated immune response is the objective, maintaining a balance during both innate and adaptive immune responses should be considered as well. Further studies are highly recommended to assess the outcomes of such interventions. The battle against covid-19: where do we stand now? 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