Lung mucosal immunity to NTHi vaccine antigens: Antibodies in sputum of chronic obstructive pulmonary disease patients

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory illness in older adults. A major cause of COPD-related morbidity and mortality is acute exacerbation of COPD (AECOPD). Bacteria in the lungs play a role in exacerbation development, and the most common pathogen is non-typeable Haemophilus influenzae (NTHi). A vaccine to prevent AECOPD containing NTHi surface antigens was tested in a clinical trial. This study measured IgG and IgA against NTHi vaccine antigens in sputum. Sputum samples from 40 COPD patients vaccinated with the NTHi vaccine were collected at baseline and 30 days after the second dose. IgG and IgA antibodies against the target antigens and albumin were analyzed in the sputum. We compared antibody signals before and after vaccination, analyzed correlation with disease severity and between sputum and serum samples, and assessed transudation. Antigen-specific IgG were absent before vaccination and present with high titers after vaccination. Antigen-specific IgA before and after vaccination were low but significantly different for two antigens. IgG correlated between sputum and serum, and between sputum and disease severity. Sputum albumin was higher in patients with severe COPD than in those with moderate COPD, suggesting changes in transudation played a role. We demonstrated that immunization with the NTHi vaccine induces antigen-specific antibodies in sputum. The correlation between IgG from sputum and serum and the presence of albumin in the sputum of severe COPD patients suggested transudation of antibodies from the serum to the lungs, although local IgG production could not be excluded.

Clinical Trial Registration: NCT02075541

Plain Language Summary

What is the context?

• Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory illness in older adults and the third leading cause of death worldwide.

• One bacterium in the lungs, non-typeable Haemophilus influenzae (NTHi), is responsible for acute exacerbation of the disease, characterized by an increase in airway wall inflammation and symptoms, leading to high morbidity and mortality.

• A vaccine targeting NTHi was previously developed but did not show efficacy in reducing exacerbations in COPD patients, probably because the vaccine did not elicit an immune response in the lung mucosae, where the bacteria are located.

What is the impact?

• Parenteral immunization with new vaccines targeting NTHi is able to elicit immune defense at the level of lung mucosae.

• Now that antibodies can be measured in sputum, new vaccines against COPD exacerbations or other lung infections can be tested for efficacy in the actual target tissue.

• Also, lung immunity against specific pathogens can now be tested.

What is new?

• We determined that antigen-specific antibodies were present in the lungs after vaccination; these were assessed in sputum after vaccination with NTHi surface antigens.

• NTHi-specific IgG were present in the lungs and appeared to have arrived there primarily by transudation, a type of leakage from the serum to the lung mucosae.

• Transudation appeared to be stronger in severe than in moderate COPD patients.

KEYWORDS:

• COPD exacerbations
• COPD pathology
• bacterial infection
• respiratory infection
• infection control

Abbreviations

AECOPD	=	Acute exacerbation of COPD
BAL	=	Bronchoalveolar lavage
BSA	=	Bovine serum albumin
COPD	=	Chronic obstructive pulmonary disease
IgA	=	Immunoglobulin A
IgG	=	Immunoglobulin G
Mcat	=	Moraxella catarrhalis
NTHi	=	Non-typeable Haemophilus influenzae
OVA	=	Ovalbumin
PBS	=	Phosphate-buffered saline
PD	=	Protein D
PE	=	Protein E
PilA	=	type IV pilin subunit protein

Acknowledgments

The authors would like to thank Ilaria Galgani and Sonia Schoonbroodt (GSK) for their contribution to the study.

The authors thank Business & Decision Life Sciences Medical Communication Service Center for editorial assistance and manuscript coordination on behalf of GSK. Esther van de Vosse, on behalf of GSK, provided writing support.

Disclosure statement

AKA, CB, DS, FB, LM, MB, MCo, OF, SA, SL, SR, and SRP are employed by GSK. AKA, LM, MB, MCo, SR, and SRP hold shares in GSK. The authors declare no other financial and non-financial relationships and activities. MCa declare no financial and non-financial relationships and activities and no conflicts of interest.

Contributorship

FB, CB, SR, MB and SRP were involved in the study conception and design. CB, SA, and MCa were involved in acquisition and generation of data. FB, CB, SA, SL, LM, MB and SRP were involved in data analysis and FB, CB, MCo, SR, AKA, MB, LM, OF, DS, and SRP were involved in data interpretation.

All authors contributed substantially to the development of the manuscript and had full access to the data. All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this article.

Data availability statement

GSK makes available anonymized individual participant data and associated documents from interventional clinical studies which evaluate medicines, upon approval of proposals submitted to www.clinicalstudydatarequest.com. To access data for other types of GSK sponsored research, for study documents without patient-level data and for clinical studies not listed, please submit an enquiry via the website. Clinical trial registration is NCT02075541.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2343544

Trademark

AS01 is a trademark owned by or licensed to GSK.

Additional information

Funding

GlaxoSmithKline Biologicals SA funded this study and was involved in all stages of study conduct, including analysis of the data. GlaxoSmithKline Biologicals SA also took in charge all costs associated with the development and publication of this manuscript.