This paper by Paessler and Veljkovic on the potential link between bradykinin-2 receptor (BKB2R) and influenza virus is an interesting, as well as a provocative follow-up of previous work by this group published in 2014 ¹ . In that paper, sequence homology between influenza virus and human proteins was investigated by the informational spectrum method (ISM analysis). BKB2R, although it didn’t get the highest amplitude or signal:noise values on the IS frequency, was studied in more detail because of its association with cardiovascular disease. It should be noted that conventional BLASTing of BKB2R with a range of influenza A strains (including A/Beijing/262/95 (H1N1), A/NewCaledonia/20/1999(H1N1)), shows very limited sequence homology. Thus far there is no direct evidence that influenza vaccination induces antibodies (agonistic or antagonistic) that would bind to BKB2R, but is interesting to speculate about possible consequences.

Bradykinin, signaling via BKB2R (as well as BKB1R) is an important regulator molecule in inflammatory and vascular processes including angioedema, tissue permeability, vascular dilation, and smooth muscle contraction. Bradykinin also has been shown to promote proliferation and invasion of cancer cells, as indicated in the manuscript.

Indeed, natural or experimental infection with influenza virus induces bradykinin secretion, which can be measured in nasal secretions during the first days after onset of symptoms (before specific antibodies are formed) ² . In the above context, this would argue in favor of vaccination to prevent influenza infection.

The immunogenicity and safety (including potentially negative effects) of influenza vaccination in (pediatric) patients with cancer have been published: NCT00112112 ³ , NCT00906750 ⁴ . In an accompanying editorial of latter study, the need for influenza vaccination of children with cancer is emphasized ⁵ .  Most studies have limited follow-up, related to the seasonal nature of influenza vaccination. Prolonged monitoring of vaccinees therefore is warranted.

Patients with solid tumors are treated with chemotherapy and/or checkpoint inhibition therapy. From that perspective, BKB2R agonists have been investigated as adjuvant therapy. While being effective in animal models ⁶ , thus far it is not being used in patients.

It could be concluded that the intricate relation between bradykinin and influenza, also in the context of vaccination of patients with cancer required further study. Current clinical and immunological data however would not support a safety concern.

Is the topic of the opinion article discussed accurately in the context of the current literature?

Yes

Are arguments sufficiently supported by evidence from the published literature?

Partly

Are all factual statements correct and adequately supported by citations?

Partly

Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Yes

Reviewer Expertise:

medical immunology (GTR), oncology (MW), influenza vaccination (both)

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.

In this article, the authors suggest that flu vaccine could elicit antibodies against BKB2R. This, in turn, would lead to BKB2R activation and, therefore, activate/reinforce pro-tumoral pathways.

The suggestion for the possible generation of anti-BKB2R antibodies comes from an in silico work of the authors and is supported by the observation that BKB2R monoclonal antibodies inhibit influenza virus replication in cell lines (data from a patent).

These considerations are not solid enough to advise against the flu vaccination of cancer patients.

Moreover, the authors should clearly state in the text that there are no experimental data yet supporting their suggestion for anti-BKB2R antibodies production upon flu vaccination.

The authors suggest that BKB2R antibodies would activate the receptor. However, reasoning in the same way, these antibodies should also inhibit BKB2R, or mediate immune response toward cells expressing this receptor, thus showing anti-cancer properties. This latter is another point of view that should be considered in the discussion.

Taking together, these considerations suggest that advise against the flu vaccination is premature, while further studies that aim to clarify if the vaccine against influenza A viruses could elicit agonistic antibodies for BKB2R are needed and could have an impact on flu vaccination choice as well as on cancer treatments.

Is the topic of the opinion article discussed accurately in the context of the current literature?

Partly

Are arguments sufficiently supported by evidence from the published literature?

Partly

Are all factual statements correct and adequately supported by citations?

Yes

Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Yes

Reviewer Expertise:

NA

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.