The role of bacterial vaccines in the prevention of influenza mortality
Authors: Keith P Klugman, Shabir A Madhi, Amy Sarah Ginsburg, Gail L Rodgers
Journal: The Lancet Global Health (2018)

The 100th anniversary of the 1918 influenza pandemic has arrived without a human proof-of-concept universal influenza vaccine to prevent the next pandemic. World Pneumonia Day, on Nov 12, is a good time to reflect on our improved understanding of the role of bacterial coinfections in deaths from seasonal and pandemic influenza virus, and the potential of bacterial vaccines, particularly pneumococcal conjugate vaccine (PCV) and possibly future vaccines against Staphylococcus aureus, to mitigate pandemic influenza mortality. During the 1918 pandemic, abundant evidence from cultures of blood, lungs, and pleural fluid from both living individuals and from post-mortem specimens showed a substantial contribution of bacterial coinfections to mortality from the pandemic influenza virus.1Morens DM Taubenberger JK Fauci AS Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness.J Infect Dis. 2008; 198: 962-970Crossref PubMed Scopus (1121) Google Scholar, 2Chien YW Klugman KP Morens DM Bacterial pathogens and death during the 1918 influenza pandemic.N Engl J Med. 2009; 361: 2582-2583Crossref PubMed Scopus (92) Google Scholar Although inactivated bacterial vaccines were claimed at the time to prevent influenza, a claim inconsistent with the viral cause of the pandemic, some data suggest that such bacterial vaccines might have prevented some of the 1918 influenza-associated mortality.3Chien YW Klugman KP Morens DM Efficacy of whole-cell killed bacterial vaccines in preventing pneumonia and death during the 1918 influenza pandemic.J Infect Dis. 2010; 202: 1639-1648Crossref PubMed Scopus (41) Google Scholar The contribution of bacterial infection to influenza mortality during the 2009 influenza A H1N1 pandemic included evidence of bacterial infection among 43% of pandemic influenza deaths in children across the USA;4Centers for Disease Control and PreventionSurveillance for pediatric deaths associated with 2009 pandemic influenza A (H1N1) virus infection—United States, April–August 2009.MMWR Morb Mortal Wkly Rep. 2009; 58: 941-947PubMed Google Scholar 55% of influenza victims in New York, NY, USA;5Gill JR Sheng ZM Ely SF et al.Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infections.Arch Pathol Lab Med. 2010; 134: 235-243Crossref PubMed Google Scholar 38% of pandemic influenza deaths in Brazil;6Mauad T Hajjar LA Callegari GD et al.Lung pathology in fatal novel human influenza A (H1N1) infection.Am J Respir Crit Care Med. 2010; 181: 72-79Crossref PubMed Scopus (429) Google Scholar 56% of hospital admissions for severe disease or deaths in Argentina;7Palacios G Hornig M Cisterna D et al.Streptococcus pneumoniae coinfection is correlated with the severity of H1N1 pandemic influenza.PLoS One. 2009; 4: e8540Crossref PubMed Scopus (220) Google Scholar and 46% of severely ill patients in intensive care units infected with proven pandemic influenza A H1N1 illness in France.8Cuquemelle E Soulis F Villers D et al.Can procalcitonin help identify associated bacterial infection in patients with severe influenza pneumonia? A multicentre study.Intensive Care Med. 2011; 37: 796-800Crossref PubMed Scopus (80) Google Scholar The impact of PCV on influenza-associated hospital admissions was first described in a randomised trial of an investigational nine-valent PCV, in which recipients of the vaccine had a 45% (95% CI 14–64; p=0·01) reduction in hospital admissions associated with seasonal influenza virus in Soweto, South Africa, from 1998 to 2001.9Madhi SA Klugman KP A role for Streptococcus pneumoniae in virus-associated pneumonia.Nat Med. 2004; 10: 811-813Crossref PubMed Scopus (317) Google Scholar The roll-out of a seven-valent PCV in the USA was associated with similar statistically significant annual reductions of between 39% and 50% in influenza-associated hospital admissions of infants younger than 2 years, from 2000 to 2004.10Simonsen L Taylor RJ Young-Xu Y Haber M May L Klugman KP Impact of pneumococcal conjugate vaccination of infants on pneumonia and influenza hospitalization and mortality in all age groups in the United States.MBio. 2011; 2: e00309-e00310Crossref PubMed Scopus (187) Google Scholar A subsequent case–control study in South Africa, including the 2009 pandemic A H1N1 season and extending through the 2012 influenza season, found that completion of the PCV schedule in children younger than 5 years was associated with a 26% reduction in hospital admissions due to influenza-associated acute respiratory illness (case population ratio 0·74, 95% CI 0·71–0·77).11Abadom TR Smith AD Tempia S Madhi SA Cohen C Cohen AL Risk factors associated with hospitalisation for influenza-associated severe acute respiratory illness in South Africa: a case-population study.Vaccine. 2016; 34: 5649-5655Crossref PubMed Scopus (39) Google Scholar Furthermore, a case control study in Spain during the pandemic season from 2009 to 2010 showed a 48% (95% CI 1–76) reduction in influenza-associated hospital admissions, but not in the subsequent season (2010 to 2011) during which PCV vaccine coverage was high in both influenza-infected and control individuals.12Dominguez A Castilla J Godoy P et al.Benefit of conjugate pneumococcal vaccination in preventing influenza hospitalization in children: a case-control study.Pediatr Infect Dis J. 2013; 32: 330-334Crossref PubMed Scopus (9) Google Scholar Data from a model of the 1918 influenza pandemic in a contemporary setting with access to PCV and antibiotics suggest a substantial effect of widespread PCV coverage in infants on reducing pandemic influenza mortality in all ages.13Chien YW Levin BR Klugman KP The anticipated severity of a "1918-like" influenza pandemic in contemporary populations: the contribution of antibacterial interventions.PLoS One. 2012; 7: e29219Crossref PubMed Scopus (17) Google Scholar In addition to PCV immunisation helping to protect infants from influenza-associated hospital admission during a future influenza pandemic, adult lives could be saved through herd protection. The only randomised trial (to our knowledge) of PCV use in adults also addressed the question of prevention of influenza-associated hospital admissions in a secondary analysis, and found an estimate of efficacy in prevention of hospital admissions due to community-acquired pneumonia associated with influenza, in line with that observed in the paediatric PCV trial.14Huijts SM Coenjaerts FEJ Bolkenbaas M et al.The impact of 13-valent pneumococcal conjugate vaccination on virus-associated community-acquired pneumonia in elderly: exploratory analysis of the CAPiTA trial.Clin Microbiol Infect. 2018; 24: 764-770Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar 23 first episodes of community-acquired pneumonia associated with influenza were observed in the 13-valent PCV group and 35 in the placebo group for a vaccine efficacy of 34·4%; however, as this outcome was a secondary analysis for which the trial was not powered, the efficacy was not statistically significant (95% CI −11·1 to 61·2, p=0·117). With support from government, industry, and several foundations in this 1918 centennial anniversary year, the possibility of developing a universal influenza vaccine and substantially decreasing the burden of pneumonia mortality is very exciting. In the meantime, the increased and welcome roll-out of PCV in all countries, now including low-income and middle-income countries, is likely to provide some protection against the inevitable mortality associated with the next influenza pandemic.15Smil V The next 50 years: fatal discontinuities.Polpul Dev Rev. 2005; 31: 201-236Crossref Scopus (22) Google Scholar We declare no competing interests. The disgraceful neglect of childhood pneumoniaThis week WHO held its first ever Global Conference on Air Pollution and Health and published an associated report , Prescribing clean air, which summarised the "uniquely damaging" effects of breathing polluted air on the health of children. The evidence in this age group is compelling: some of the stark headline figures include the fact that 93% of children younger than 5 years globally live in environments where levels of fine particulate matter (PM2.5) exceed the WHO guidelines and that air pollution, both ambient and household, contributed to more than half a million deaths from lower respiratory tract infections in children under 5 years in 2016. Full-Text PDF Open Access