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

Date Vaccine composition Trial type Number of participants Result

1914 Whole 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

Date Vaccine composition Trial type Number of participants Result

1944 Polysaccharide 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 ConnectionRobert Austrian, MD, 1917-2007

http://www.historyofvaccines.org/content/robert-austrian-1

• 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 VaccinationStrategies Using Pneumococcal

ConjugateVaccine Compared With Pneumococcal

Polysaccharide VaccineJAMA. 2012;307(8):804-812

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

INCREFF

INCRCOST FREQ PRO-

PORTIONC1 IV IE>0 IC<0 Superior 0 0C2 I IE>0 IC>0 ICER<50k 106 0.0212C3 III IE<0 IC<0 ICER>50k 0 0C4 I IE>0 IC>0 ICER>50k 1 2.00E-04C5 III IE<0 IC<0 ICER<50k 0 0C6 II IE<0 IC>0 Inferior 4893 0.9786Indiff origin IE=0 IC=0 0/0 0 0

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 ConclusionIn 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.