**4.4 The potential clinical applications of TIbVs in the context of viral outbreaks**

The non-specific mechanism of TIbVs against widely differing pathogens associated to the induction of trained immunity can be exploited clinically. This makes TIbVs as a ready-to-act tool to tackle disease outbreaks from different angles where conventional specific vaccines have proven their limitations:

*Newly emerging disease outbreaks, with no conventional vaccines available.* Even in the presence of therapeutic options, vaccines are the best tool to prevent infections. However, even with worldwide efforts, getting a vaccine to the public takes time. In addition, side effects, dosing issues, and manufacturing problems can all cause delays [3]. Herein, using available TIbVs could mitigate the devastating consequences of emergent outbreaks by means of non-specific protection, until a suitable specific vaccine is available.

*Newly emerging disease outbreaks, first coming vaccines with partial efficacy.* Even if a vaccine gets available to the market, conventional strategies might raise some issues. The unpredictable identity of largely unknown emerging pathogens, the lack of appropriate experimental animal models, and the time for faster developing may give raise to an upcoming vaccine with no full efficacy [3]. On the other hand, limitations of current vaccines, such as mumps, also include a low efficacy resulting from an unacceptable drop in the immune response over time, requiring re-immunization [145]. In these contexts, the administration of a TIbV prior to the specific vaccine may enhance the response to the latter (111).

*Re-emerging disease outbreaks, pathogens with high mutation rates and loss of vaccine efficacy.* Mutations are the building blocks of evolution in any organism. Viruses are among the fastest evolving entities, especially RNA viruses such as influenza. Implications in conventional vaccine design are numerous, as a high mutation rate makes it hard to design a vaccine that is universally effective across many years. As a result, this makes a vaccine effective for shorter and raises the need for yearly vaccination programs [22, 146]. Since the underlying mechanism of TIbVs extend well beyond their nominal antigens and have a broad-spectrum of protection, TIbVs could overcome the troublesome of highly specific vaccines that promote antigen variant switching [147].

*Disease outbreaks in vulnerable populations.* During infectious disease outbreaks, vulnerable populations are usually disproportionately affected due to an interplay of immunological, epidemiological, and medical factors, which leads to sub-optimal or even under-vaccination [148]. This is well exemplified in the elderly population, where successful vaccination against important infectious pathogens which cause high morbidity and mortality represents a growing public health priority. Age-related immunosenescence and 'inflammaging' have been postulated as underlying mechanisms responsible for decreased response and high mortality, including during COVID-19 pandemic or influenza season [80, 149]. Therefore, more potent vaccines are needed. In this regard, the induction of trained immunity by the use of TIbVs is proposed to overcome the immune dysfunction found in these individuals [28]. Thus, elderly has been proposed as one of the groups to benefit from the use of TIbVs, including severe COVID-19 disease, with the aim of potentiating the immunogenicity of their vaccination [80]. Moreover, some types of immunodeficiencies or immunosuppression may benefit from TIbVs. These formulations, by means of tackling both branches of immunity, especially the innate compartment, may be an achievable alternative to reinforce protection or optimize immunogenicity of vaccination in this population [130, 139].

Altogether, harnessing the TIbV concept has been suggested as a crucial step in future vaccine development and implementation, because a wide range of clinical applications may benefit to some extent from their use [150].

#### **4.5 TIbVs in the time of COVID-19**

Despite the tremendous financial and scientific effort invested to rapidly obtain a prophylactic vaccine against SARS-CoV-2, only the first one has been licensed in December 2020. Although this means less than a year since the declaration of the pandemic by the WHO, which is an unprecedented achievement, in the meantime, two pandemic waves of COVID-19 and more than 1.5 million deaths have been declared worldwide. Therefore, alternative strategies have been considered to fill the gap until a safe and effective vaccine is available. As noted earlier in this chapter, TIbVs can play an important role for this purpose by increasing host resistance to other pathogens, including viruses.

A bunch of recent studies have been published supporting the role of certain vaccines, including BCG, OPV and measles, as a possible successful strategy to reduce susceptibility and severity to SARS-CoV-2 through trained immunity induction [80, 151, 152]. Thus, clinical trials are currently being conducted to find out the contribution of trained immunity as a preventive tool in the context of COVID-19 pandemics [153]. In a prospective observational trial, 255 MMR vaccinated subjects were followed searching for COVID-19 cases, thirty-six presented COVID-19 but all with a remarkable mild course [154]. Recent studies have also suggested a potential benefit of influenza vaccine on the susceptibility and the outcome of certain infections including SARS-CoV-2. In this sense, a particular attention has been focused on a high-risk population, the elderly. In a study conducted in Italy, influenza vaccination in people aged 65 and over was associated with a reduced spread and a less severe clinical expression of COVID-19 [155].

Finally, in addition to the potential role of TIbV conferring resistance against SARS-CoV-2 infection, they can eventually be used to increase efficacy of specific anti-COVID-19 vaccines, when available, especially in vulnerable population. In this sense, implications of vaccination route and mucosal immunity have also been raised as a key aspect in the development of safe and effective prophylaxis interventions against SARS-CoV-2. Most formulations in development are parentally administered; only a few COVID-19 vaccine candidates are administered by mucosal routes. Still, studies indicate that even if mucosal immunization against coronavirus does not confer sterilizing immunity, the ability to induce anti-SARS-CoV-2 IgA responses in the airways may prevent virus spread to the lung and avoid respiratory distress [156]. In this regard, mucosal TIbVs could enhance the mucosal response of specific COVID-19 vaccines acting as TIbAs by combining them as pointed above in those especially vulnerable subjects.

### **5. Conclusions and future perspectives**

Viral outbreaks can cause epidemics and pandemics if the route of transmission allows for the rapid virus spread. Given the ease of travel and the global exchange of potential transmitting agents, these situations will be increasingly frequent in the future. Preventing the spread of a virus outbreak caused by a highly contagious agent is not easy in the absence of effective therapies or preventive measures. Although the development of effective prophylactic vaccines specific for the threatening virus is the final goal when possible, this requires a minimum time of almost a year in the best possible scenario. Meanwhile, the consequences of the spread of a deadly virus can be devastating, as it is exemplified during the COVID-19 pandemic. This scenario may also take place in the case of re-emerging viruses tackled by partial efficacious vaccines. In such situations, harnessing the heterologous non-specific protection of some existing vaccines with a known safety track record

#### *Trained Immunity-Based Vaccines: A Ready-to-Act Strategy to Tackle Viral Outbreaks DOI: http://dx.doi.org/10.5772/intechopen.95765*

is an interesting possibility. This protection may be critical for vulnerable subjects and/or for highly exposed individuals, like healthcare workers.

Non-specific protection of some vaccines is thought to be mainly dependent on their effect on the innate immune system. Increasing evidence gathered over the past few years points that innate immune cells show memory-like features when properly activated. This memory termed "trained immunity" has been associated with the non-specific protection of vaccines. The concept of "trained immunitybased vaccine" (TIbV) has been drawn to exploit the potential of trained immunity in designing novel vaccines or to redefine bacterial-derived preparations conferring broad protection against widely differing pathogens. As trained immunity may have implications on the adaptive immune response and *vice-versa*, its potential to provide enhanced immune responses is quite broad whether considering natural infections or following vaccination.

Taken advantage of the current COVID-19 pandemic, a number of clinical trials have been launched with putative TIbVs in order to address protection in highly exposed subjects. The results are eagerly expected as these initiatives may be considered as a proof-of-concept supporting their use in future epidemics/pandemics to fill the gap until a specific vaccine is available. Nevertheless, as trained immunity can be achieved by different inducers, it is unlikely to obtain the same degree of protection, duration, etc. for all of them, which may also depend on the biological behavior and the route of transmission of the threatening pathogen. As in most instances rapidly spreading viruses are airborne and primarily infect the mucosa of the airway tract, induction of trained immunity at the local mucosal level can confer a more adequate protection. This may be an opportunity for mucosal TIbVs as compared to those given parenterally.

Trained immunity may justify heterologous protection of vaccines, help to explain their underlying mechanisms, open avenues for next generation of vaccines, or be proposed to tackle outbreaks by new pathogens as described here. However, this is an emerging field that requires more clinical data before being a reality in the clinical practice; not only to be used against infectious outbreaks, but to fight against recurrent infections in vulnerable subjects for whom no effective vaccines are yet available.
