Bromhexine Prophylaxis and Pharmacologically Attenuated Natural Immunization: A Personalized Host-Directed Strategy Against SARS-CoV-2 and Influenza

Background: Bromhexine hydrochloride (BRH) has been proposed to functionally inhibit the host serine protease TMPRSS2, a key mediator of viral entry for SARS-CoV-2, influenza A and B viruses, and other respiratory viruses that depend on TMPRSS2-mediated proteolytic activation. Emerging evidence suggests that the antiviral activity of BRH against SARS-CoV-2 may extend beyond TMPRSS2 inhibition. BRH may interfere with spike–ACE2 interaction through ACE2-targeted mechanisms, while preliminary molecular and computational evidence suggests probable inhibition of the SARS-CoV-2 main protease (Mpro/3CLpro), potentially affecting viral polyprotein processing and replication. Thus, BRH may exert a three-pronged antiviral effect against SARS-CoV-2—interference with spike–ACE2 binding, inhibition of TMPRSS2-dependent viral entry, and probable inhibition of Mpro/3CLpro-dependent viral replication. Rather than completely preventing infection, such multimodal pharmacological attenuation may reduce viral entry and amplification while preserving sufficient antigen exposure for adaptive immune priming. This strategy may be particularly relevant to personalized prevention according to individual susceptibility, comorbidities, exposure risk, and vulnerability to severe respiratory infection. Methods and Clinical Observations: We describe a 72-year-old man who had received no SARS-CoV-2 vaccination 2021 and had been taking BRH prophylactically (8 mg twice daily) for approximately two weeks before an incidentally diagnosed SARS-CoV-2 infection. The infection remained clinically inapparent apart from mild throat irritation. Despite the absence of clinically significant disease, he developed a robust humoral immune response, with an anti-spike antibody concentration of 2,080 BAU/mL three months after infection and persistent anti-spike IgG reactivity nine months later (Vircell anti-S IgG ratio 22.209). A parallel household observation involved his 71-year-old wife, who had multiple established risk factors for severe COVID-19, including chronic obstructive pulmonary disease, previous pancreaticoduodenectomy for pancreatic cancer, severe underweight, and a long history of heavy smoking. Despite continuous BRH prophylaxis and presumed household exposure, she remained clinically asymptomatic while demonstrating measurable anti-spike immune reactivity. Additional real-world observations from individuals receiving prolonged BRH prophylaxis—including elderly patients with multiple comorbidities, heavy smokers, and a child receiving seasonal prophylaxis—were characterized by favorable tolerability and absent or markedly attenuated clinically apparent COVID-19 and influenza. Hypothesis and Conclusions: These observations support the hypothesis of Pharmacologically Attenuated Natural Immunization (PANI), whereby pharmacological attenuation of infection reduces viral entry and subsequent amplification sufficiently to limit tissue injury and clinically significant disease without necessarily producing sterilizing protection, thereby preserving antigen presentation and adaptive immune priming. In SARS-CoV-2 infection, the proposed three-pronged activity of BRH—targeting spike–ACE2 interaction, TMPRSS2-dependent entry, and potentially Mpro/3CLpro-dependent replication—provides a mechanistic framework for such controlled attenuation. For influenza, the principal proposed mechanism remains inhibition of TMPRSS2-dependent hemagglutinin activation. Within a personalized medicine framework, this concept raises the possibility of tailoring host-directed prophylaxis according to individual risk profiles. The observations presented here are hypothesis-generating and do not establish causality. Prospective controlled studies incorporating documented viral exposure, serial quantitative virological assessment, neutralizing antibody measurements, cellular immune profiling, and predefined risk stratification are required to determine whether BRH can reproducibly achieve infection sufficient for immune priming but pharmacologically constrained below the threshold for clinically significant disease.