www.ncirs.usyd.edu.au www.ncirs.usyd.edu.au

Prof Robert Booy NCIRS, Marie Bashir Institute, Uni of Sydney

Comparing the effectiveness of polysaccharide & conjugate pneumococcal vaccines in bacteremic & non-bacteremic pneumonia among older adults:

focus on pneumococcal pneumonia

June 2017

Conflict of interest statement

Robert Booy has been an advisor &/or received funding from Romark, Vaxxas, bioCSL/Sequiris, Roche, Sanofi, GlaxoSmithKline (GSK), Novartis, Baxter, Pfizer, Merck & Astra Zeneca to conduct sponsored research, or to attend present at scientific meetings He has on occasions received honoraria for delivering educational presentations Any funding received is directed to a research account at Children’s Hospital at Westmead, not personally accepted

6-valent polysaccharide vaccines registered 1940s

§  Development of penicillin arguably set back pneumococcal vaccine research by decades!

§  The ‘original’ 13 valent (plain polysaccharide) pneumococcal vaccine was highly efficacious against pneumococcal disease, whether bacteremic or not

- A plain polysaccharide vaccine without conjugation

The Clinical Efficacy of an Experimental 13-valent Pneumococcal Polysaccharide Vaccine in

South African Gold Miners

Condition Vaccine Efficacy (%) p value

Pneumococcal bacteremia1 82.3 <.0001

Putative pneumococcal pneumonia1, 2 78.5 <.0001

Radiologically diagnosed pneumonia3 53.0 <.0001

Pneumococcal vaccine (13-valent) was given to 1493 subjects and meningococcal vaccine or placebo to 3007 subjects. 1 Vaccine-type pneumococcal infection. 2 Sputum-culture positive; 3 All pneumonias, with or without isolation of pneumococci from the sputum

•  Austrian R et al. Trans Assoc Amer Phys 1976; 89: 184-94 •  Younger, healthier adults; vaccines had higher antigen content

What do we now know about pneumococcal vaccine effectiveness against pneumonia in adults?

§  The last 2 years have seen even more systematic reviews of the published (and unpublished) data

§  Diao Vaccine 2016 Vaccine – immuno-competent adults §  Kraicer-Melamed 2016 Vaccine – general population >50yrs §  Schiffer-Rohe 2016 PLoS One – adults at increased risk §  Falkenhorst 2017 Plos One - adults 60+ §  And a Cochrane revision is in preparation

§  There are now even more systematic reviews, than RCTs §  Also, many observational studies - variable quality §  Do we now see through a glass less darkly? – Rorschach

comes to mind

We all see indistinct shapes and interpret them differently – and different people focus visually on different parts of the picture, so experts have different conclusions..

New Testament, Bible 1 Corinthians 13:12

“Through a glass darkly”

St Paul: At the end of time we will see clearly!

But maybe not by end of this talk

www.ncirs.usyd.edu.au

Context: Community-acquired Pneumonia Immunization Trial in Adults (CAPITA) in The Netherlands and Australian proposal to use PCV13 in elderly

• The Dutch Health Council had never recommended PPV23 for older adults and PPV23 use was very low •  These unique circumstances were used to justify a randomized, placebo-controlled trial (CAPITA) of PCV13 to prevent CAP in 85,000 community-dwelling elderly people - a VIP study • The investigators said, “this trial will be critical to determine the position of conjugate pneumococcal vaccines in the prevention of pneumococcal disease.” Hak E Neth J Med 2008 Dutch investigators and their sponsors did not take the opportunity to compare vaccine efficacy of PPV 23 and PCV13 in preventing both IPD and CAP

Per protocol analysis: 45.6% efficacy for Vaccine-type community acquired pneumonia

High Quality Research on PPV23: Cochrane R/V Moberly… Andrews 2013 18 RCTs §  Invasive (bacteremic) pneumococcal disease OR 0.26; they added

observational studies as IPD is a rare outcome §  All-cause (CXR diagnosed) pneumonia:

low income OR 0.54 (0.43-0.67) high income OR 0.71 (not significant)

§  No benefit on mortality Observational studies were EXCLUDED in assessing impact of vaccine on non-bacteremic pneumonia (due to protocol restrictions) We do now know more about pneumococcal disease & its’ prevention

Risk of bias assessment

§  Random sequence generation §  Allocation concealment §  Blinding §  Incomplete outcome data &

Selective reporting §  Confounding (non-RCT)

Only five RCTs determined to have overall low risk of bias: Austrian 1980 Maruyama Ortqvist Riley Russell

VE against Pneumonia (all-causes)

Moberley et al. Cochrane Systematic Review (2011 unpublished)

Adults in low income countries

favours Vaccine

favours Control

46% (33%,57%)

I2 19%

VE (95%CI)

P

6v 13v

14v 12v

Vaccines used in 4 RCTs

14562 participants

VE against Pneumonia (all-causes)

Moberley et al. Cochrane Systematic Review (2011 unpublished)

Adults in high income countries with chronic illness

favours Vaccine

favours Control

7% (-19%,27%)

I2 10%

VE(95%CI)

?

23v 14v 4010 participants

Vaccines used in 6 RCTs

VE against Pneumonia (all-causes)

Moberley et al. Cochrane Systematic Review (2011 unpublished)

favours Vaccine

favours Control

Adults in high income countries (otherwise healthy adults)

29% (-12%,55%)

I2 93%

VE (95%CI)

?

12v 6v

3v 2v

23v 14v

29186 participants

Vaccines used in 6 RCTs

Factor Group 1 Group 2 Group 3

Immunogenicity +++ + ++

Etiological agent detection

+++ + +?

Disease susceptibility + +++ ++

Risk of exposure +++ ++ +

Serotype distribution + +++ ++

Serotype coverage +++ + +

Power of studies +++ + +

Cochrane finding of VE + - ?

Why the difference between groups?

§  Largest, most recent RCT Russell et al 2015 n=152,723 •  Follow-up 9 to 12 weeks (only) •  Institutional setting – military recruits •  Estimated 12% attrition, 11/1000 attack rate, 20% pneumonia

caused by Spn, 90% of Spn caused by vaccine type and vaccine 70% efficacious

•  What they found: 7% attrition, 2.5/1000 incidence rate, 0% pneumonia identified as Spn

•  Despite very large sample size, no real change in VE for prevention all-cause pneumonia

One new study

No benefit in recent RCTs in rich countries for prevention

Questions remain

-  Under-powered

-  Likely benefit in some groups

-  Unable to rule out efficacy <42%

Cochrane conclusions re PPV efficacy against adult/elderly

pneumonia

§  Publication of analysis used by STIKO, Germany (ATAGI-like) §  Systematic R/V & meta-analysis of vaccine efficacy or

effectiveness of PPV23 against IPD & pneumococcal pneumonia (PP) in adults >60 years in developed countries

17 eligible studies §  After exclusion of ‘highly biased’ studies,

VE for PP was 64% (35-80%) in 2 clinical trials 48% (25-63%) in 2 cohort studies

§  Excluded 2 trials that used only serologic diagnosis

German meta-analysis Falkenhorst PLoS One, 2017

Meta-analyses of RCTs for IPD or pneumococcal pneumonia (Falkenhorst et al 2017)

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VEIPD = 73% (10 –92%)

VEPP = 64% (35 – 80%)

Most or all PP diagnosed with insufficiently validated pneumolysin tests eg Ortqvist and Honkanen Low specificity

Meta-analyses of observational studies, IPD (Falkenhorst 2017)

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VEIPD = 58% (38 – 72%)

VEIPD = 45% (15 – 65%)

VEIPD = 59% (35 – 74%)

VEVT-IPD = 73% (56 84%)

VEVT-IPD = 37% (45 – 27%)

Meta-analyses of observational studies, pneumococcal pneumonia (Falkenhorst 2017)

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VEPP = 37% (12 – 55%)

VEPP = 53% (33 – 68%)

VEPP = 48% (25 – 63%)

just a few and mainly Spanish studies – cf Cochrane PP is becoming a rarer outcome

Overview of recent meta-analyses of 23vPPV effectiveness (Falkenhorst 2017)

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Duration of protection is also an important issue Pletz et al 2017, Lancet ID commenting on Suzuki paper

and Maruyama paper

§  We need to consider the observation time when analysing randomised controlled trials of PPV23

§  The high efficacy of PPV23 reported by Maruyama and colleagues might be explained by the very high incidence of pneumococcal pneumonia around the time of vaccination and the cessation of the observation period briefly after the vaccine efficacy started to diminish

§  Vaccine effectiveness against PPV23-type in Suzuki paper for pneumococcal pneumonia was 37·7% (95% CI 4·8–59·2) within the first 2 years after vaccination, and declined to no significant effectiveness (34·7% [–7·4 to 60·3]) after the second year

§  UK colleagues are re-evaluating their observational data

Suzuki 2017: 23vPPV effectiveness over time

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Pneumococcal pneumonia

Adjusted VE* (95* CI)

All 27.4% (3.2 – 45.6%)

23vPPV - type 33·5% (5·6 - 53·1 %)

13vPCV - type 40·1% (9·9 to 60·2)

*Adjusted for study site, sex, age, underlying disorder, smoking status, pre-hospital antibiotic treatment, and year of hospital visit.

Characteristics of observational studies for pneumococcal pneumonia (Falkenhorst 2017 plus Suzuki 2017)

Study   Study type  

Country   Study population1  

Time from vaccination  

Number of vaccinated/

unvaccinated  

VE against pneumococcal

pneumonia (95% CI) 2  

(Vila-Corcoles

et al., 2006)3  

Cohort   Spain   Resident population, aged ≥65 years  

Variable (87% 2–5

years)  

17,401/16,504 (person-years)  

45% (12–66%)4  

(Ochoa-Gondar et al., 2014)  

Cohort   Spain   Resident population, aged ≥60 years  

Up to 5 years  

29,065/46,968 (person-years)  

51% (16–71%)  

(Vila-Corcoles

et al., 2009)  

Case-control  

Spain   IPD and PP cases ≥50 (74% ≥65 years and matched controls  

Up to 7.5 years  

304/608   48% (27–63%)  

(Wiemken et al., 2014)  

Case-case  

USA, Europe  

CAP cases ≥65 years  

No information  

279 pneumococcal CAP/ 2,409 CAP due to other or unknown

etiology  

37% (16–60%)  

(Suzuki et al., 2017)  

Test-negative design case-

control  

Japan   Pneumonia cases ≥65 years  

Up to 5 years  

419 pneumococcal pneumonia (272 23vPPV type, 72 non-23vPPV, 75

untyped)/ 1,617 non-pneumococcal

pneumonia  

27% (3–46%)

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One final issue

§  Conjugate vaccines are very effective in children and are associated with strong herd immunity effects

§  As in Goldblatt, Lancet Global Health 2017

Herd immunity impact of childhood PCV program (Shiri Lancet Global Health 2017)

Recent review and meta-analysis of herd immunity impact of childhood vaccination estimates time to 50% and 90% reduction in serotype specific IPD

Law of diminishing returns: how much disease caused by “13 valent serotypes” will be left to be prevented if PCV13 used for the elderly? Much to begin with.. But for how long?

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Age Serotypes Years to 50% Reduction

Years to 90% Reduction

65+ 7vPCV 2.6 (2.3 – 3.0) 8.9 (7.9 – 10.3)

13vPCV not 7vPCV

4.1 (2.6 – 7.4) 10.3 (6.4 – 20.7)

All 7vPCV 2.3 (1.9 – 2.7) 8.9 (7.8 – 10.3) 13vPCV not 7vPCV

3.6 (2.5 – 6.1) 9.5 (6.1 – 16.6)

Predicted IPD cases in the 60+ population predicted by German dynamic transmission model (Kuhlmann)

GS1: PCV7 GS2: PCV13 / not PCV 7 / not ST 3 GS3: ST 3 GS4: PPSV23 / not PCV 13 GS5: Other

Pneumococcal Disease in Adults: A health economics evaluation of various vaccination scenarios in Germany. Final Report . A Kuhlmann, M Treskova and J-M Graf von der Schulenburg. German version available at: http://www.rki.de/DE/Content/Infekt/Impfen/Forschungsprojekte/abgeschlossene_Projekte/Pneumokokkenerkrankungen/Abschlussbericht.pdf?__blob=publicationFile ; Accessed 16/6/2017

IPD Quarterly Report 1Oct-31Dec 2016

Conclusions

§  Many meta-analyses with variable results, depending on which studies included – controversy continues

§  RCT evidence supports good benefit against IPD of vaccines, polysaccharide or conjugate

§  RCT evidence supports moderate benefit against pneumococcal CAP (not bacteraemic) if studies using pneumolysin tests are excluded

§  Some recent observational studies suggest moderate benefit from PPV23 in preventing pneumococcal CAP

§  Dutch RCT shows good protection against pn CAP §