CONJUGATE PNEUMOCOCCAL VACCINE
Dr. Nitin Shah*
Consultant Pediatrician, PD Hinduja National Hospital Editor, IAP Textbook of Pediatrics, Editor, Immunization in Clinical Practice.*
Introduction: Pneumococcus is a common organism causing invasive bacterial disease, especially in children < 2 years and elderly adults. In the west, now it is the commonest organism causing invasive bacterial disease, as Hib is virtually eradicated with universal Hib vaccination. Interest existed in developing pneumococcal vaccine since 1940s till penicillin became available. With the emerging resistance to penicillin and other drugs, there is resurgence of interest in pneumococcal vaccine, especially after the success of conjugation technique. This has led to availability of highly efficacious conjugate pneumococcal vaccine which is creating history in western world.

Pneumococcus: Pneumococcus has more than 90 serotypes grouped into more than 45 serogroups. (1) Most serotypes do not have cross protection. Of these, 10 serotypes cause> 90% of childhood infections and include serotypes 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 3, 7.(1) Of these, type 1 is the commonest serotype in India as per IBIS study.(2)

Disease Spectrum: Pneumococcus can lead to invasive diseases like bacteremia, meningitis, pneumonitis or local infections like non-bacteremic pneumonia, acute otitis media, cellulites, arthritis, peritonitis etc. 30-50% of children of school age are carriers for one or more serotypes. In adults, carrier rate varies from 6-30%. From nasopharyngeal carrier state, it can spread locally or systemically leading to clinical disease. In west, the first contact with pneumococcus occurs at 6 months of age whereas in developing countries it can occur as early as 17 days! The peak incidence of pneumococcal disease is at 6-24 months of age.

Incidence of invasive disease varies from 25-50 / 100,000 children <5 years in Europe to 90 / 100,000 <5 year in USA to 500 / 100,000 <5 years in Gambia and Apache Indians.(3)

90% of bacteremia, 30-50% of pneumonia, 30-45% of pyogenic meningitis and 30-60% of all bacterial AOM are caused by pneumococcus. The mortality rate of invasive disease is 6-20% and there are sequelae like CNS sequelae in survivors of meningitis and deafness in children with recurrent AOM.

It is estimated that in USA, annually pneumococcus leads to 3000 cases of meningitis, 50,000 cases of bacteremia, 500,000 cases of pneumonia and 7 million cases of AOM with 40,000 deaths. (1) In India, it is estimated that pneumococcus leads to 50,000 - 75,000 cases of meningitis. (4) IBIS study showed that of the pneumococcal invasive diseases 30% present as meningitis, 30% as pneumonia and 30% as bacteremia, peritonitis and others. (2) At this rate one expects pneumococcus to cause 50,000 - 75,000 cases of invasive pneumonia, 50,000 - 75,000 cases of other types of invasive disease, 10 times more cases of non-bacterial pneumonia and 100 times more cases of AOM.

Bacterial Resistance: First cases of penicillin resistance were reported in 1970s. Since then the resistance has spread world over. Countries like Sri Lanka and Taiwan have > 40% of serotypes penicillin resistant, USA and Europe have 10-40% resistance, and India and Australia have <10 % resistant serotypes, IBIS study showed that intermediate penicillin resistance was seen in 1-4% of serotypes in India. The resistance has been increasing over last 2 decades. In USA it increased from 4% in 1980 to 30% in 1990.

Pneumococci are resistant to other drugs too like TMP/SMX, Chloramphenicol, and even 3 rd generation cephalosporins.

Serotypes 6B, 9V, 14, 19F and 23F are responsible for most of the resistant infections and are covered by the 7 valent vaccine. Infection with resistant forms means use of higher dose of antibiotic or use of alternate drugs like Cefotaxime or Vancomycin to prevent mortality. One of the main reasons for increasing resistance is misuse of antibiotics. (5)

Unconjugated Pneumococcal Vaccines: 23 valent plain polysaccharide vaccine is available since last few decades. Being non-T cell dependent it can not induce good immune response. The immune response is IgM type; short lived; has low titers, affinity, avidity; has no local IgA immunity and does not have boosting effect inspite of repeated doses.

Hence, this vaccine can not be used below 2 years of age when it is most required. At best it has efficacy of 70% in healthy adults against invasive disease and only 56% in those> 65 years of age. It has poor efficacy against non-bacteremic pneumonia and doubtful if any efficacy against AOM, carrier state or immune compromised hosts.

Conjugated Pneumococcal Vaccine : After the success of conjugated Hib vaccine, the next obvious target was conjugated pneumococcal vaccine. Initially, 1, 2, 4 & 5 valent vaccines were tested and found highly effective. Now 7, 9 and 11 valent vaccines have been tried and of this 7 valent CRM 197 conjugated vaccine (Prevenar) is commercially available in west. Other carrier proteins tried include Tet Toxoid, Diphtheria toxoid and OMP of meningococcus. None of them are commercially available at present
Content: 7 valent vaccine contains 2 μg of each serotypes 4, 9, 14, 18C, 19F, 23F and 4 ug of 6B, that is total of 16 μg of antigen in 0.5 ml of vaccine. 9 valent vaccine contains additional serotypes 1, 5 and 11 valent vaccine in addition has serotypes 3, 7. (6)

Safety: 7 valent conjugate vaccine given to infants is a very safe vaccine. Mild local reactions are seen in 30-35% of patients and include redness, warmth, pain, induration and tenderness. Severe local reactions of> 2.5 cm diameter are seen in 5-6% of patients. The reactions are less than those seen with DPwT and same as seen with DpaT, Hib/MMR vaccines. These is no increase in side effects with increasing serotypes or number of doses. (7, 8)
Fever of > 38 degree C is seen in 25-35% of recipients whereas fever of > 39 degree C is seen in < 5% of patients. Rare adverse reactions like febrile convulsion, breath holding spasms are same as seen with any other vaccine and are more of a coincidence. Severe adverse reactions are unknown to occur with this vaccine (7, 8) .

Immunogenicity: Rise in GMT following 3 primary doses is statistically better than controls for each serotype in vaccine with 4.4 to 27.0 fold rise in titers. 92-100% of vaccines develop GMT of> 0.15 µg/ml and 91-90%> 1.0 μg/ml. Pre-booster titers are better than pre-primary titers for all serotypes. Post-booster titers rise by 5-15 fold. GMT rises to 2.3 - 9.7 μg/ml and 96-100% recipients have GMT of> 0.15 μg/ml and 84-100%> 1.0 μg/ml. Types 4 and 6B are the most immunogenic serotypes. (8)
Efficacy in field trails: The ultimate proof of any vaccine is in its performance in a field trial. Many such trails have been conducted on conjugate pneumococcal vaccine including the 7 valent vaccine.

Invasive Disease: Study done by Black et al in California, USA compared CRM 197 pneumococcal vaccine (Prevenar) with conjugated meningococcal C vaccine used as placebo. (8) It was given in a schedule of 3 primary doses at 2, 4, 6 months followed by a booster at 12-15 months. All other routine vaccine like OPV/IPV, DPwT/DpaT, Hib, MMR, Varicella were given at other sites simultaneously as required. The 3 year long study enrolled nearly 38,000 babies. The CRM 197 pneumococcal vaccine showed 97.4% efficacy till April '95 which continued to be 97.8% at 1 year FU till July 2000. It was 100% for serotypes 14, 18C, 23F, 9V, 84.6% for 19F and 83.7% for 6B. Most failures occurred with 19F and 6B. (8)

Pneumonia: The same study done by Black et al also looked at efficacy against clinically diagnosed pneumonia. (8) The efficacy was 11.4% against any pneumonia diagnosed clinically, 13.8% against any pneumonia with X-ray taken, 33% against any pneumonia with some abnormalities on X-ray and 63% against pneumonia with consolidation of> 2.5 cm on X-ray of chest (which is likely to be caused by pneumococcus more than other pathogens).

Acute Otitis Media : Besides the study done by Black et al, one more study by Eskola et al looked at efficacy against AOM. They studied culture proved cases of AOM by doing myringotomy in patients diagnosed to have AOM with middle ear fluid as per WHO guidelines. (9)
Both the studies found nearly similar efficacy. Efficacy against any AOM episode was 7.8% to 8.9% which was little less than expected efficacy of 9.6 - 16.2%. It means protection against AOM needs both higher GMT and local immunity. Efficacy against AOM caused by vaccine serotypes was 57 - 66.7%. The efficacy against frequent AOM was 9.3% for frequency of 3 episodes / 6 months or 4 episodes / year and rose to 22.8% for frequency of 5 episodes / 6 months or 6 episodes / year. Efficacy in cases requiring placement of drainage tube was 20.1%. This means efficacy was better against cases with frequent AOM or AOM needing tube placement as there are usually caused by resistant serotypes covered well by the vaccine,

Carrier State and Herd Immunity: Studies done using conjugated tetravalent vaccine given at 2, 4, 6 months followed by a booster does of unconjugated pneumococcal vaccine by Dagan et al showed 5% carrier rate by Tet. Toxoid conjugated vaccine, 10% by Diphtheria toxoid conjugated vaccine as compared to 27% in controls. (10) Similar results were seen using CRM 197 conjugated 5 valent vaccine in infants by Obera et al (11) and by Dagan et al in order children .(12) However, these studies also found some increase in carriage of non-vaccine serotypes. However, this has not led to increase in clinical cases and hence is not a clinical problem.

Schedule: Children presenting before 7 months of age are given 3 primary doses at 2, 4 and 6 months or 2, 3, 4 months or at 6, 10, 14 weeks depending on local schedule, and a booster at 12-15 months. Children coming between 7-12 months are given 2 primary doses at 4-8 weeks interval and a booster at 12-15 months. Children presenting between 12-24 months are given 2 doses at 4-8 weeks interval and those coming after 24 months till 5 years of age are given a single dose of the vaccine. It is given IM over deltoid or lateral aspect of thing. It is to be stored at 2-8 o C and the shelf life is 2 years.

Problems and future: Main problem is coverage of prevailing serotypes. 7 valent vaccine will have coverage of> 90% serotypes in USA, 75% in Europe, 51% in India, and 45% in Pakistan. Similar figures with 9 valent vaccine will be 71% in India, 30% in Dhaka (Bangladesh) and 61% in Pakistan and with 11 valent vaccine 75% in India, 51% in Dhaka, and 61% in Pakistan. Hence we need 9 or 11 valent vaccine for good global coverage.

The other problems are high cost which needs to come down. There may be need to increase the dose of some antigens like 19F serotype. Lone term follow up will prove the efficacy over years and need for further booster if any. For timely completion it has to be given simultaneously along with other childhood vaccines. Some studies of combined CRM 197 vaccine along with HbOC/DPT have proved it be safe and efficacious. We need more studies on such combinations. We also need clear cut studies showing its benefits in older children, adults and immune compromised hosts esp. HIV infected patients. Study done in Africa using 9 valent vaccine has shown good efficacy inspite of high prevalence of HIV in children. (9) Lastly, we need to update the prevailing serotypes. For this we need continued surveillance of pneumococcal disease globally.
References :
  1. Black S, Sheinfield H. Progress toward effective pneumococcal vaccination in infancy. Contemporary Pediatrics 1998, Pg. 12-17.
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  6. Prevenar. Information booklet published by Wyeth-Ayerest Laboratories 2001, March
  7. Black S, Shinefield SH, Fireman B et al. Efficacy safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatric Infect Dis J 2000; 19:187-195.
  8. Rennels MB, Bedwards KM, Keyserling H et al. Safety and immunogenicity of Heptavalent pneumococcal vaccine conjugated to CRM 197 in United States infants. Pediatrics 1998, 101:604-611.
  9. Eskola J, Kilpi T, Palmu A et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N. Engl J Med 2001;344:403-409
  10. Dagan R, Mullaem M, Melamed R et al. Reduction of pneumococcal nasopharyngeal carriage in early infancy after immunization with tetravalent pneumococcal vaccine conjugated to either tetanus toxoid or diphtheria toxoid. Pediatr Infect Dis J 1997;16:1060-1064.
  11. Obaro SK, Abdegbola RA, Banya WA et al. Carriage of pneumococci after pneumococcal vaccination. Lancet 1996;348:272.
  12. Dagan R, Melamed R, Muallem M et al. Reduction of nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent conjugate pneumococcal vaccine. J Infect Dis 1996;174:1271-1278.
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