Developing a Vaccine against Pneumonia, “The Captain of Death” -- Osler

History 1881 Louis Pasteur discovers the pneumococcus bacterium 1886 Gold mining begins in South Africa 1895 Pneumococcus identified as the cause of epidemic pneumonia that kills 35% of miners who are infected 1904 Miners strike for health reasons, including pneumonia 1910 Treatment with ethylhydrocuprein, a quinine derivative, is found to be too neurotoxic 1911 Mine owners hire the developer of typhoid fever vaccine to develop a pneumococcal vaccine

Important Early Vaccine Studies DateVaccine compositionTrial type Number of participants Result 1914Whole cell, heat-killed organisms Prospective, placebo- controlled, non randomized trial with 1 yr follow-up 50,000 South African miners Not reported, but vaccine given to all miners

Therapies Other Than Vaccine 1920s through 1940s antiserum – Gram stain sputum to confirm cause – Identify strain (Neufield reaction) – Give strain-specific horse or rabbit antiserum intravenously – Problems included severe allergic reactions and prolonged delays identifying strain and obtaining antiserum for treatment 1938 Sulfapyridine – Problems included vomiting and severe rash

Therapies Other Than Vaccine 1920s through 1940s antiserum – Gram stain sputum to confirm cause – Identify strain (Neufield reaction) – Treat with strain-specific horse or rabbit antiserum intravenously – Problems included severe allergic reactions and prolonged delays identifying strain and obtaining antiserum for treatment 1938 Sulfapyridine – Problems included vomiting and severe rash

Next Major Vaccine Study DateVaccine compositionTrial type Number of participants Result 1944Polysaccharide types 1,2,5,7 made by E.R.Squib & Sons Placebo-controlled, randomized with 6 mo follow- up 17,000 members of the US Air Force 90% effective

More History 1941 First reported use of penicillin to treat pneumonia in humans 1945 FDA approves penicillin 1946 FDA approves Squibb vaccine 1951 Squibb stops making its vaccine because no one is using it

The Penn Connection Robert Austrian, MD,

Austrian suspected that serious risks from pneumococcal infection persisted despite the prevalence of antibiotics, and he produced the evidence needed to persuade a skeptical medical community. After a study of patients in New York City’s Kings County Hospital from 1952 to 1962, Austrian concluded that the incidence of pneumococcal pneumonia was much higher than was thought at the time and that the mortality rate of 15% in bacteremic cases was unchanged, despite antimicrobial treatment. In 1962, Austrian left the State University of New York College of Medicine at Brooklyn to join the University of Pennsylvania. There, he developed a new vaccine and conducted clinical trials among gold miners in South Africa that found the vaccine safe and efficacious. The recent emergence of widespread resistance of pneumococcus to commonly used antibiotics highlights the incredible importance of the vaccine. What he did to solve a major human disease problem, often almost totally by himself, is extremely rare in modern medicine. – Paraphrased from the obituary by Harvey Freidman in JCI

Current Vaccines Pneumococcal conjugate vaccine – Polysaccharides conjugated with diphtheria proteins to enhance immunogenicity – Active against 13 strains – Abbreviated PCV13 Pneumococcal polysaccharide vaccine – Not conjugated – Active against 23 strains – Abbreviated PPSV23

Current Vaccine Recommendations for Infants, Toddlers, and Children Pneumococcal conjugate vaccine (PCV13) is recommended for all infants, toddlers, and children from 2 months through 5 years of age. It also is recommended for children 6 through 18 years of age with certain medical conditions regardless of whether they have previously received a pneumococcal vaccine.

Current Vaccine Recommendations for Adults Pneumococcal polysaccharide vaccine (PPSV23) is recommended for adults 65 years and older; for younger adults who have a chronic illness or who smoke; for Alaska Natives and certain American Indian populations; for people who had their spleen removed; and for those with weakened immune systems.

Important Observations In elderly adults, PPSV23 protects against invasive pneumococcal disease (IPD) but perhaps not against nonbacteremic pneumococcal disease (NPD) In children, PCV13 protects against IPD and NPD The effect on adult disease from childhood vaccination is unknown

Cost-effectiveness of Adult Vaccination Strategies Using Pneumococcal Conjugate Vaccine Compared With Pneumococcal Polysaccharide Vaccine JAMA. 2012;307(8):

What Do We Know about the Journal and the Authors?

Vaccination Strategies Modeled No vaccination PPSV23 at age 65 (current recommendation) PCV13 at age 65 PCV13 at age 50, and PPSV23 at age 65 PCV13 at age 50 and again at age 65 PCV13 at age 50 and again at age 65 plus PPSV23 at age 75

Model Features Life-time horizon Societal perspective 3% discount rate for costs and benefits Quality of life measured on 0 to 1 scale, and QALYs calculated by multiplying the utility of a state times the duration in that state

Model Inputs from Table 1 Vaccine effectiveness Vaccine adverse events Disability – risk and mortality Utility weights by age and level of risk Hospitalization rates and costs by type of disease (IPD vs. NPD) Vaccine costs

Results in Table 3

Henry’s Efficient Algorithm

Results in Table 3

Deterministic Sensitivity Analyses One-Way Only

More Results in Table 3

How to Describe the Results of Probabilistic Sensitivity Analyses: Could these results have occurred by chance alone? Plot results of separate Monte Carlo runs as a cloud in the cost-effectiveness plane Calculate p-values or confidence intervals Create cost-effectiveness acceptability curve

Step 4. Analyze the “Stochastic” Tree

Sampling

Cost-Effectiveness Plane

Incremental CE Plot Report QUAD- RANT INCR EFF INCR COSTFREQ PRO- PORTION C1IVIE>0IC<0Superior00 C2IIE>0IC>0ICER<50k C3IIIIE<0IC<0ICER>50k00 C4IIE>0IC>0ICER>50k12.00E-04 C5IIIIE<0IC<0ICER<50k00 C6IIIE<0IC>0Inferior IndifforiginIE=0IC=00/000

Do You Agree with the Authors’ Conclusion? Overall, PCV13 vaccination was favored compared with PPSV23, but the analysis was sensitive to assumptions about PCV13 effectiveness against nonbacteremic pneumococcal pneumonia and the magnitude of potential indirect effects from childhood PCV13 on pneumococcal serotype distribution.

My Translation of the Authors’ Conclusion In the base case analysis and in most of the deterministic sensitivity analyses, PCV13 vaccination was favored compared with PPSV23, but the analysis was sensitive to assumptions about PCV13 effectiveness against nonbacteremic pneumococcal pneumonia and the magnitude of potential indirect effects from childhood PCV13 on pneumococcal serotype distribution.

Two Problems with This Conclusion In the base case analysis and in most of the deterministic sensitivity analyses, PCV13 vaccination was favored compared with PPSV23, but the analysis was sensitive to assumptions about PCV13 effectiveness against nonbacteremic pneumococcal pneumonia and the magnitude of potential indirect effects from childhood PCV13 on pneumococcal serotype distribution. 1.This conclusion does not help readers decide whether there is a preferred vaccine strategy, and if so, which one it is. 2.This conclusion ignores the probabilistic sensitivity analysis.

What about this Alternative Conclusion? In the base case analysis and in most of the deterministic sensitivity analyses, the strategy of giving PCV13 at age 50 and again at age 65 was favored over other strategies, but our probabilistic sensitivity analysis showed that the differences between this strategy and other strategies could have occurred by chance alone.