Counterpoit By Horwin “For example, in the article entitled Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in Children. Northern California Kaiser Permanent Vaccine Study Group (Pediatr Infect Dis J 2000 Mar;19(3); 187-95), Black, Shinefield et al claim an efficacy of Prevnar of over 97%. There were 40 cases of pneumococcal disease (39 in control group and 1 in Prevnar group). Therefore the control group accounted for 97.5% of the children with pneumococcal disease (39/40 = 97.5%). Compared to the control group, Prevnar was 97.5% effective. But these are relative percentages and present a confusing message regarding absolute efficacy and value of the vaccine. For example, imagine your child had a .0000000000000000001 chance of getting a disease (18 zeros). And the vaccine reduced this rate to .000000000000000000001 (20 zeros). Based on Black and Shinefield's approach (relative percentage) this hypothetical vaccine is actually 99.9% effective. But, as a parent I would be most interested in the absolute value of the vaccine. "Tell me my child's risk of getting the disease if I don't vaccinate. Tell me my child's risk of getting the disease if I do vaccinate." According to Lederle's data from the package insert, if you don't vaccinate with Prevnar the risk is approximately 20 in 100,000 (0.020%) for all persons, and 150 in 100,000 (0.15%) for children under two. If you do vaccinate with Prevnar, the risk decreases to 3 out of 18,906 (.016). If you vaccinate with the control vaccine, the risk is 27 out of 18,910 (0.14%). By looking at this comparison, Prevnar provides an absolute value of 0.13% (0.15 - 0.016 = 0.13%) compared to no vaccination, and 0.12% (0.14 - 0.016 = 0.12) compared to the control. (In fact, the data may already be skewed in favor of Prevnar because the Prevnar and control figures were for various ages of children but the comparison without the vaccine is being made to infants. This inflates the comparative efficacy of Prevnar because infants have a higher rate of pneumococcal disease compared with older children.)” Counterpoint When Prevnar® was endorsed and licensed in the United States in 2000 only one efficacy trial had been done according to the American Academy of Pediatrics Technical Report. The research reported by Black, Shinefield et al in “Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children” [ Pediatric Infect Dis J 2000; 19:187-195] was funded at least in part by the vaccine manufacturer. ***** Adverse Effects and Safety From the AAP Technical Report The PCV7 vaccine has been associated with an acceptable incidence of adverse effects when given at 2, 4, 6, and 12 to 15 months of age with concurrent administration of recommended, age-appropriate vaccines (diphtheria and tetanus toxoids and acellular pertussis [DTaP], H influenzae type b conjugate [HbOC], diphtheria and tetanus toxoids and pertussis [DTP]/HbOC, hepatitis B, oral poliovirus [OPV], inactivated poliovirus [IPV], and measles-mumps-rubella [MMR] and varicella vaccine), compared with the administration to children of a control investigational vaccine of meningococcal C polysaccharide conjugated to CRM 197 . 54 No hepatitis A vaccine has been given concurrently with PCV7. Available data suggest that PCV7 may prove to be among the most reactogenic (eg, local reactions and incidence of fever) vaccine of those currently used, including the DTaP and Haemophilus conjugate vaccines. Moderate local reactions (any erythema Counterpoint Comparing the adverse events of Prevnar® to those of an “investigational conjugate meningococcal vaccine” the researchers who performed the clinical trials estimated that Prevnar was associated with an acceptable incidence of adverse events. Prevnar was actually licensed and endorsed by the AAP Committee on Infectious Diseases without anyone really knowing how it compared with sterile water or saline injections. The AAP Technical Report statement in 2000 that Prevnar® may prove to be “the most reactogenic” vaccine of the era – even more reactogenic than DTaP and HIB is noted with interest. On September 17, 2006 , a review of the Vaccine Adverse Event Reporting System (VAERS) files revealed that there had been 376 reports of death filed following the administration of Prevnar® vaccine alone or with other vaccines. All 376 reports were reviewed. It must be again stated that reports to VAERS describing events following vaccination do not prove that such events were due to the administered vaccine. It seems more likely than not, that deaths described in the following reports may have been related to the administration of Prevnar®. VAERS ID 158751 Vaccination Date: 2000-07-27 Age 0.8 Date filed: 2000-08-15 Sex M Where Administered: PVT State WI Purchased by: PVT Life Threatening Illness? No Died? Yes (date died: 2000-07-28) Disability? No Recovered? No ER or Doctor Visit? No Hospitalized? No Current Illness: Sinusitis Diagnostic Lab Data: Previous Vaccinations: Other Medications: Preexisting Conditions: Walker-Warburg syndrome
Vaccinations Manufacturer Lot Dose Route Site 1 PNC LEDERLE 475228 1 IM LL Onset Date: 2000-07-28 Days since Vaccination: 1 Symptoms: REACT UNEVAL Death. Doubt any relationship other than temporal.
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VAERS ID 161756 Vaccination Date: 2000-07-03 Age 0.8 Date filed: 2000-11-10 Sex M Where Administered: PVT State KY Purchased by: Life Threatening Illness? Yes Died? Yes (date died: 2000-07-22) Disability? No Recovered? No ER or Doctor Visit? Yes Hospitalized? Yes (days in hospital: 2) Prolonged Hospitalization? No Current Illness: Diagnostic Lab Data: sepsis work-up, CSF culture showed strep pneumoniae; CSF was sent to CDC where it was sterotyped as #14, which is a sterotyped contained in Prevnar Previous Vaccinations: Other Medications: Tylenol, Motrin Preexisting Conditions:
Vaccinations Manufacturer Lot Dose Route Site 1 PNC LEDERLE 4712149 0 IM LL Onset Date: 2000-07-19 Days since Vaccination: 16 Symptoms: DYSPNEA FEVER HYPOXIA INFECT BACT INTRACRAN HYPERTENS MYDRIASIS PNEUMONIA RASH STUPOR VOMIT On 7/19, the pt developed a fever and rash on face. On 7/20, the fever continued. On 7/21, the pt developed vomiting and fever. Then later on 7/21, seen at physician's office with unresponsiveness, forced respirations, bulging fontanelle, dilated left pupil. Pt transferred by ambulance to hospital where pt was intubated. En route to CT, the pt was coded and eventually expired on 7/22.
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VAERS ID 165790 Vaccination Date: 2001-01-11 Age 0.2 Date filed: 2001-02-13 Sex M Where Administered: State SC Purchased by: Life Threatening Illness? No Died? Yes (date died: 2001-01-14) Disability? No Recovered? No ER or Doctor Visit? No Hospitalized? Yes (days in hospital: ) Prolonged Hospitalization? No Current Illness: Diagnostic Lab Data: Previous Vaccinations: Other Medications: Preexisting Conditions: prematurity (29 weeks), ROP
Vaccinations Manufacturer Lot Dose Route Site 1 PNC LEDERLE IM Onset Date: 2001-01-11 Days since Vaccination: 0 Symptoms: APNEA CYANOSIS SHOCK This patient presented to ED in shock. The patient was then transported to PICU. The patient in shock requiring cardiopulmonary resuscitation. The patient expired approximately 72 hours after admission. The patient had received Prevnar the day prior to admission. Autopsy shows baby was cyanotic, not breathing
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VAERS ID 169943 Vaccination Date: 2001-04-24 Age 0.3 Date filed: 2001-05-21 Sex M Where Administered: PVT State CA Purchased by: PUB Life Threatening Illness? No Died? Yes (date died: 2001-04-25) Disability? No Recovered? No ER or Doctor Visit? No Hospitalized? No Current Illness: NONE Diagnostic Lab Data: Previous Vaccinations: Other Medications: NONE Preexisting Conditions: NONE
Vaccinations Manufacturer Lot Dose Route Site 1 PNC LEDERLE 473343 1 IM LL Onset Date: 2001-04-25 Days since Vaccination: 1 Symptoms: PNEUMONIA INTERSTIT STUPOR Infant died in sleep. ***
VAERS ID 171974 Vaccination Date: 2001-03-13 Age 1.3 Date filed: 2001-06-19 Sex M Where Administered: PVT State WA Purchased by: PUB Life Threatening Illness? No Died? Yes (date died: 2001-03-21) Disability? No Recovered? No ER or Doctor Visit? No Hospitalized? No Current Illness: Diagnostic Lab Data: CBC; UA/UC; Chem Panel; Blood culture; Head CT; Abdominal CT; CXR Previous Vaccinations: Other Medications: Preexisting Conditions: Hg C trait; Septic elbow; Septic hip; anemia; inguinal hernias; Atopic dermatitis
Vaccinations Manufacturer Lot Dose Route Site 1 PNC LEDERLE 474724 1 IM LL Onset Date: 2001-03-21 Days since Vaccination: 8 Symptoms: ANOREXIA CONVULS FEVER MENINGITIS SEPSIS VOMIT Came in the ER with complaint of fever, low appetite, vomiting, had seizure in ER and unstable. Transport to other facility was arranged and pt expired during transport. Pneumococcal sepsis and meningitis. ***
VAERS ID 178823 Vaccination Date: 2001-11-14 Age 2.0 Date filed: 2001-12-11 Sex F Where Administered: PUB State OH Purchased by: PUB Life Threatening Illness? No Died? Yes (date died: 2001-11-17) Disability? No Recovered? No ER or Doctor Visit? No Hospitalized? No Current Illness: NONE Diagnostic Lab Data: Previous Vaccinations: Other Medications: NONE Preexisting Conditions: NONE
Vaccinations Manufacturer Lot Dose Route Site 1 PNC LEDERLE 484131 1 IM LL Onset Date: 2001-11-17 Days since Vaccination: 3 Symptoms: VOMIT The evening of 11/16/01 , the child vomited X 1 and no other symptoms were present. The child died in her sleep that night. Cause of Death as per autopsy report was SIDS with focal epiglotitis. Note : Acute pneumococcal epiglottitis has been described. The death of a baby with epiglottitis and almost certainly bacteremia should not be attributed to SIDS .
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VAERS ID 184907 Vaccination Date: 1996-10-17 Age 2.6 Date filed: 2002-05-21 Sex M Where Administered: UNK State Purchased by: UNK Life Threatening Illness? No Died? Yes (date died: 1999-01-04) Disability? No Recovered? No ER or Doctor Visit? No Hospitalized? Yes (days in hospital: ) Prolonged Hospitalization? No Current Illness: Acute Myeloid leukemia NOS; Immunodeficiency NOS Diagnostic Lab Data: Blood culture 11/15/98-specimen revealed penicillin resistant Streptococcus pneumoniae serotype 19F; Culture NOS-(+) right pleural effusion grew Aspergillus; Differential WBC-2.3, 12% neutrophils, 88% lymphocytes; Full blood count 11/10/98- Previous Vaccinations: Other Medications: Preexisting Conditions: Epistaxis episodes since the age of 14 months; Per F/U 5/28/02 history of acute myeloid leukemia; immunodeficiency NOS Vaccinations Manufacturer Lot Dose Route Site 1 PNC LEDERLE LABORATO 3 IM Onset Date: 1998-11-15 Days since Vaccination: 759 Symptoms: ANEMIA DYSPNEA EFFUS PLEURAL FEVER HEM GI INFECT BACT INFECT FUNG LEUKEMIA CHRON MYELO LEUKOPENIA MENINGITIS SEPSIS Information has been received from an investigator concerning a male child with a history of acute myeloid leukemia who received his 4th dose of Prevnar on 10/17/96 as part of a post-marketing safety surveillance trial. Approx. 2 years, post vax, at 31 months of age, he developed sepsis. Culture revealed Streptococcus pneumoniae serotype 19F. Sepsis was considered to be an "Other Medically Important Event". The Medical Monitor and Investigator's assessment of the relatedness between septicemia streptococcal Note : Streptococcus pneumoniae serotype 19F is a Prevnar vaccine strain.
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VAERS ID 231321 Vaccination Date: 2004-08-23 Age 0.9 Date filed: 2004-12-21 Sex F Where Administered: MIL State FL Purchased by: MIL Life Threatening Illness? No Died? Yes (date died: 2004-08-27) Disability? No Recovered? No ER or Doctor Visit? No Hospitalized? No Current Illness: NONE Diagnostic Lab Data: Autopsy with diffuse eosins throughout all tissues. Death due to bronchiolitis/abdominal distention. Previous Vaccinations: Other Medications: NONE Preexisting Conditions: Syndactyly
Vaccinations Manufacturer Lot Dose Route Site 1 PNC LEDERLE LABORATO 494313 2 IM LL Onset Date: 2004-08-27 Days since Vaccination: 4 Symptoms: ABDO ENLARGE APNEA BRONCHIOLITIS HYPERVENTIL HYPOXIA Pt presented to clinic 5 days after immunization with abdominal distention, tachypnea, decreased sats, developed repiratory failure in ER and subsequently intubated. Pt died. *** In addition, the VAERS review revealed that there were:
*** As reviewed in “The Next Storm”, problems found during pre-licensure trials in South Africa , Israel and Gambia were neither publicized nor seriously considered when the Prevnar® vaccination program was launched in the United States . http://www.cdc.gov/ncidod/eid/vol5no3/lipsitch.htm ***** Cost Effectiveness Analysis From the AAP Technical Report The potential cost-effectiveness of a routine pneumococcal conjugate vaccine program in healthy children has been evaluated. 65 Based on an annual birth cohort of 3.8 million infants, it was assumed that routine PCV7 immunization would prevent 78% of annual pneumococcal meningitis cases ( n = 2219), 69% of annual bacteremia cases ( n = 52 319), and 7% of annual otitis media cases ( n = 1 009 505). This would result in net savings to society, if the cost of each dose of vaccine was Counterpoint The cited reference 65 is: Lieu TA, Ray GT, Black SB, Projected cost-effectiveness of pneumococcal conjugate vaccination of healthy infants and young children. JAMA 2000; 283:1460-1468 The AAP Technical Report failed to mention that the “Conclusions” of the study by Lieu, Ray et al were: “Pneumococcal conjugate vaccination of healthy US infants has the potential to be cost-effective. To achieve cost savings, its cost would need to be lower than the manufacturer's list price. In addition to tangible costs, the vaccine should be appraised based on the less tangible value of preventing mortality and morbidity from pneumococcal disease.” Six years later, the price of Prevnar has not changed. As of September 17, 2006 , the CDC is still paying $ 57.59 per dose and the private sector must pay $ 69.25. The total cost per child (four doses): Between $ 230.36 and $ 277.00 [http://www.cdc.gov/nip/vfc/cdc_vac_price_list.htm]
*** Prevnar ® in $$$ Wednesday, November 09, 2005 “Wyeth's Prevnar vaccine against meningitis last year became the first vaccine to reach $1 billion in sales -- mainly because it sells at more than $220 per four-shot regimen. The federal government recommends Prevnar and pays a good price for it -- as do private purchasers -- because it's the first vaccine of its type and targets a life-threatening illness.” Scott Hensley and Bernard Wysocki Jr., The Wall Street Journal http://www.post-gazette.com/pg/05313/602796.stm Saturday, July 22, 2006 “Soaring sales of Wyeth's pneumococcal vaccine Prevnar helped lift the company's revenues by 8 percent and earnings by 9 percent in the second quarter over a year earlier, the company said today. The solid results helped blunt Wall Street's questions about prospects for Wyeth's new antidepressant and birth-control pill. Wyeth shares popped up 45 cents, or about 1 percent, to $44.78 in early trading. In particular, the 60 percent increase in sales of Prevnar to $518 million for the quarter, thanks to its inclusion on Britain 's national vaccine regimen, 'blew out our international revenue estimate,' analyst Barbara Ryan, of Deutsche Bank Equity Research, wrote in a note to investors. 'We are on track for another excellent year,' Robert Essner, chairman and chief executive officer, said in a statement.” Thomas Ginsberg, Philadelphia Inquirer. http://www.topix.net/content/kri/0950329161015873997923859280272918086820 ***** September 2006 Two very recent publications should be mentioned for completion. Invasive pneumococcal disease among children in a health district of Barcelona: early impact of pneumococcal conjugate vaccine. Calbo E , Diaz A , Canadell E , Fabrega J , Uriz S , Xercavins M , Morera MA , Cuchi E , Rodriguez-Carballeira M , Garau J ; Spanish Pneumococcal Infection Study Network . “This study evaluated the impact of heptavalent pneumococcal conjugate vaccine (HPCV) on invasive pneumococcal disease (IPD) in children aged < or = 5 years in Barcelona , Spain . The incidence of IPD, vaccine uptake and prevalence of nasopharyngeal colonisation were analysed in two different periods: 1999-2001 (pre-licence period), and 2002-2004 (post-licence period). In total, 121 cases of IPD were identified. The overall incidence of IPD decreased from 96.9 cases/100,000 to 90.6 cases/100,000 (OR 0.93, 95% CI 0.69-1.26, p 0.71) between the two periods. The proportion of cases caused by non-vaccine-related serotypes (NVS) increased from 21% to 43.7% (OR 2.9, 95% CI 1.2-7, p 0.01). IPD was diagnosed in seven vaccinated children, six of whom were infected by NVS. There was a trend of diminishing prevalence of resistance to penicillin and macrolides in 2002-2004. The incidence of empyema increased from 1.7 to 8.5/100,000 (OR 4.5, 95% CI 0.91-18, p 0.06). The rate of vaccination ranged from 4.8% to 34%. It was concluded that the rates of IPD in this area did not decrease following the introduction of HPCV. The low uptake of vaccine and the greater proportion of colonisation/infection by NVS probably explain these findings. A trend of increasing empyema was also apparent. A decrease in the prevalence of penicillin and macrolide resistance paralleled the progressive uptake of vaccine.” In summary, the authors concluded:
*** Wait-and-see prescription for the treatment of acute otitis media: a randomized controlled trial. Spiro DM , Tay KY , Arnold DH , Dziura JD , Baker MD , Shapiro ED . Department of Pediatrics, Yale University School of Medicine, New Haven , Conn , USA . JAMA. 2006 Sep 13;296(10):1235-41. CONTEXT: Acute otitis media (AOM) is the most common diagnosis for which antibiotics are prescribed for children. Previous trials that have evaluated a "wait-and-see prescription" (WASP) for antibiotics, with which parents are asked not to fill the prescription unless the child either is not better or is worse in 48 hours, have excluded children with severe AOM. None of these trials were conducted in an emergency department. OBJECTIVES: To determine whether treatment of AOM using a WASP significantly reduces use of antibiotics compared with a "standard prescription" (SP) and to evaluate the effects of this intervention on clinical symptoms and adverse outcomes related to antibiotic use. DESIGN, SETTING, AND PATIENTS: A randomized controlled trial conducted between July 12, 2004 , and July 11, 2005 . Children with AOM aged 6 months to 12 years seen in an emergency department were randomly assigned to receive either a WASP or an SP. All patients received ibuprofen and otic analgesic drops for use at home. A research assistant, blinded to group assignment, conducted structured phone interviews 4 to 6, 11 to 14, and 30 to 40 days after enrollment to determine outcomes. MAIN OUTCOME MEASURES: Filling of the antibiotic prescription and clinical course. RESULTS: Overall, 283 patients were randomized either to the WASP group (n = 138) or the SP group (n = 145). Substantially more parents in the WASP group did not fill the antibiotic prescription (62% vs 13%; P<.001). There was no statistically significant difference between the groups in the frequency of subsequent fever, otalgia, or unscheduled visits for medical care. Within the WASP group, both fever (relative risk [RR], 2.95; 95% confidence interval [CI], 1.75 - 4.99; P<.001) and otalgia (RR, 1.62; 95% CI, 1.26 - 2.03; P<.001) were associated with filling the prescription. CONCLUSION: The WASP approach substantially reduced unnecessary use of antibiotics in children with AOM seen in an emergency department and may be an alternative to routine use of antimicrobials for treatment of such children In summary: • After several earlier studies seemed to show that Prevnar® decreased the incidence of acute middle ear infections and middle ear infections with effusions, it now appears that many of these infections actually improve without antibiotic treatment. 2. Providing parents with an antibiotic prescription which they may not need to use seems to be effective and avoid the use of unnecessary antibiotic. 3. Prevnar® vaccination for the prevention of ear infections does not seem justified at this time. Conclusions
The U.K. Pediatric Pneumococcal Vaccine The Next Storm http://www.jabs.org.uk/pages/nextStorm.doc
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Addendum After the above was submitted for publication, we became aware of a very recent publication in the Journal of Pediatric Infectious Diseases. Thompson LA , Irigoyen M , Matiz LA , LaRussa PS , Chen S , Chimkin F . The impact of DtaP-IPV-HB vaccine on use of health services for young infants. Pediatr Infect Dis J. 2006 Sep;25(9):826-31 BACKGROUND: In 2003, a pentavalent vaccine (diphtheria, tetanus and acellular pertussis, injectable polio and hepatitis B) was introduced into the childhood vaccination schedule. A premarketing study showed a higher incidence of fever than with the vaccines administered separately. Because fevers in young infants prompt medical evaluations, this study examines the impact of this vaccine (DTaP-IPV-HB) on subsequent use of health services. METHODS: We compared use of health services among 6- to 10-week-old infants receiving DTaP-IPV-HB (n = 1776) with a historical control receiving the prior schedule (n = 2162) at an inner-city practice network. Data sources included a hospital immunization registry and medical records. Outcome measures were visits to the emergency department and ambulatory practices, fever, tests, antibiotics and hospitalizations. Outcomes were stratified by age (<8, 8-10 weeks) and days since vaccination (3, 7). RESULTS: Infants vaccinated with DTaP-IPV-HB were more likely to visit the ED (1.2% versus 0.6%, P = 0.03) and receive tests (47.6% versus 8.3%, P = 0.03) within 3 days of vaccination compared with the controls. Multivariate analysis showed infants vaccinated with DTaP-IPV-HB had a 7-fold increased risk of receiving a full sepsis workup and a 3-fold increased risk of receiving antibiotics within 7 days of vaccination. Medical evaluations decreased over time after implementation of the DTaP-IPV-HB vaccine. Concurrently, the rate of vaccination for infants <8 weeks markedly dropped. CONCLUSIONS: The DTaP-IPV-HB vaccine was associated with increased use of health services in the emergency department, but these associations lessened over time. These findings reveal a conflict between the obligation of timely and efficient vaccination with the medical management of febrile young infants. PMID: 16940842 [PubMed - in process] Comment: As mentioned earlier, Pediarix®, the 5 in 1 vaccine used in the United States is rarely administered alone and almost always administered with Prevnar® and HIB vaccines at the 2, 4 and 6-month visits. A similar vaccination situation, Pediacel® + Prevnar® has recently been launched in the United Kingdom . F. Edward Yazbak , MD , FAAP Falmouth, Massachusetts |
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2.4 cm and/or tenderness) occurred at the injection site in 4.9% to 6.1% of children after all doses, without a statistically significant increase in the number or severity of these reactions with any subsequent dose in the series ( 
$46. Net savings to health care insurers would accrue at vaccine costs of 
$18 per dose. Additionally, a 1-dose catch-up program for all healthy children from 24 to 40 months old and those children in child care from 24 to 50 months old would result in reduced societal expenditures at a vaccine cost of 
$40/dose. The private sector cost per dose of PCV7 is ~$58/dose, or $232 for the 4 infant doses, not including administration costs. 
