What can metabolomics tell us about the efficacy of SARS-CoV-2 vaccines?
While vaccine development has been faster than for any previous emerging infectious disease, the next big challenge will be the logistics of producing and distributing hundreds of millions of doses. And since a minority of the population may not benefit from a specific vaccine, governments and health leaders must decide:
Who should get which vaccine, with which priority?
Because availability will be limited in the first few months after approval, vaccine distribution strategies will focus on limiting mortalities. Doses may be prioritized for healthcare workers and those at risk of severe disease (such as elderly patients and those with relevant co-morbidities). Fortunately, dozens of vaccines are in development, using entirely novel modes of action.
Here, we give an overview of the various modes of action of candidate vaccines (see Table 1 below), and discuss the metabolic pathways that might define the efficacy of different SARS-CoV-2 vaccination approaches. We’ll also explore the metabolites involved in shaping the functionality of the immune system (and you can find out more about these processes in our “metabolite of the month” series).
Metabolic pathways involved in the response to SARS-CoV-2 vaccines
While all vaccines are designed to prevent disease, not all can prevent infection. Vaccines which protect against infection are known to elicit “sterilizing immunity,” which means they are able to stop the virus from replicating in the body. In COVID-19, natural infection induces mucosal and systemic immunity, through IgA and IgG, respectively. IgA is thought to protect the upper respiratory tract, while the lower respiratory tract is protected by IgG (Krammer, 2020). Because SARS-CoV-2 can infect the entire respiratory system, protecting both tracts is important for achieving sterilizing immunity.
Interestingly, a gradient of ACE2 expression and SARS-CoV-2 infection levels has been found, with both showing gradual increases when moving up the respiratory system (Hou et al, 2020). These findings highlight the importance of mucosal immunity in vaccine efficacy and in achieving sterilizing immunity.
Attenuated virus and viral vector vaccines
Attenuated virus and viral vector vaccines mimic the immune response during natural infection (Su et al, 2016). By inducing both IgA and IgG responses, they are able to elicit sterilizing immunity. By contrast, vaccines administered intramuscularly or intradermally induce IgG only.
Of the 45 candidate vaccines currently in clinical evaluation, only two have potential to elicit mucosal immunity, both of which are in Phase I trials (WHO). Thus, while the first round of approved vaccines may prevent disease, it is unlikely that they will induce sterilizing immunity (Krammer 2020). It’s possible that supplementary approaches could provide an alternative path to sterilizing immunity.
Dietary fatty acids such as palmitic acid (PA) may be one way to do this. By stimulating intestinal IgA, they elicit an immune response (a common basis for oral vaccines). PA directly promotes high production of IgA in certain intestinal plasma cells and further enhances this response indirectly. In the presence of serine, PA is converted to sphingolipids (ceramides and sphingomyelin), which promote cell proliferation, survival and trafficking. This pathway is crucial for achieving high levels of intestinal IgA, and could point to PA as a potential mucosal adjuvant (Kunisawa et al 2014). However, to be useful in COVID-19 vaccines, PA-induced IgA production would need to be shown to elicit a mucosal immune response in distal sites, such as the lungs.
Involvement of metabolites in IgA and IgG responses
Mechanisms underlying variability in vaccine response are often unclear. Could a better understanding of the microbiome shed some light? The role of the microbiome in regulating immune responses and influencing vaccine efficacy is well known. Numerous vaccine clinical trials have suggested that greater microbiome diversity leads to improved immune responses following vaccination (Lex and Azizi, 2017). The gut microbiome composition established in infancy has also been shown to correlate with the development of mucosal IgA responses (Planer et al, 2016).
Metabolites produced by the gut microbiome can promote immune responses at distal sites, such as the lungs. For example, as with palmitic acid, short chain fatty acids (SCFAs) produced via gut microbial fermentation of dietary fiber, can regulate host inflammatory responses. SCFAs derived from gut microbes have been shown to protect against asthma, allergic airway disease and emphysema by promoting immune responses in dendritic cells and Treg cells in the lungs (Trompette et al, 2014; Tomoda et al, 2015; Zaiss et al, 2015).
A recent study found altered gut microbial diversity in COVID-19 patients (Gu et al, 2020). Accordingly, it was proposed that probiotics which promote gut barrier integrity by modifying the gut microbiome could potentially reduce COVID-19 GI symptoms and viral shedding (Klann et al, 2020). Considering that few vaccines in the pipeline are likely to elicit sterilizing immunity, there is a potential for continued viral shedding, even in the absence of disease (Lipsitch and Dean 2020). Probiotics or supplements of microbial-derived metabolites could be useful for those who receive vaccines which only induce systemic immunity. This could enable host metabolism to suppress viral shedding, thus preventing transmission.
Metabolic pathways and viral/viral fragment replication
As we pointed out in a recent article, viruses hijack normal cells to replicate, which may be reflected in cellular metabolism. Just like the virus, DNA/RNA-based vaccines rely on antigen replication by the host. It is thus conceivable that endogenous nucleotide metabolism may affect the response via replicative efficacy.
While purine (guanine and adenine) and pyrimidine nucleotides (cytosine, thymine, uracil) are produced by different pathways, both are affected by overall metabolism. This is highlighted by the reliance of purine synthesis on glycolysis via serine. Serine, along with the vitamin folic acid, is a key precursor of purine synthesis via one-carbon metabolism (methionine and folate cycles). The figure below shows a simplified picture of up-and downstream metabolism of nucleic acids.
Purine and pyrimidine metabolism have both been associated with outcome in COVID-19 (Wu et al., 2020). Remdesivir, licensed as a COVID-19 therapeutic in some regions, is a nucleoside analog that interferes with RNA replication, supporting the hypothesis that these processes also impact the response to DNA/RNA-based vaccines. For the pyrimidine metabolite, beta-amino-isobutyric acid, important functions in regulating lipid metabolism and inflammatory processes have been reported (Tanianskii et al., 2019)
Immune regulation, as well as viral replication, relies on a variety of metabolic processes. By extension, these processes might also be important in shaping the short- and long-term responses to SARS-CoV-2 vaccines. Due to initial supply shortages, the current situation calls for immunization strategies that lend sustained immunity after vaccination. In the medium term, this can be achieved through the availability of numerous vaccines with different modes of action, provided they are given to the appropriate individuals.
In this article, we looked at metabolic pathways associated with IgA and IgG responses, as well as nucleotide metabolism. Besides endogenous metabolism, we have explored the potential benefits of investigating host-microbiome metabolic interactions in shaping systemic and local immune responses.
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