March 2003
Vol.10 No. 2

Editors: Dr. Karen L Kwong
Drs. Elaine YW Kwan, Sam SP Lau, KY Wong

Update on Vaccines Against Respiratory Infections

Dr. Susan Chiu
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong


Editor's Notes

In this article, Dr Chiu has provided the readers a comprehensive and update information on vaccines against respiratory infections.

Summary:

Streptococcus pneumoniae is the most frequent cause of pneumonia, bacteremia, sinusitis and acute otitis media in young children. In the US, it was estimated to cause 17,000 cases invasive disease among children <5 years of age annually, including 700 cases of meningitis and 200 deaths. The highest rates of invasive disease were in children <2 years: 165/100,000 (<12 months), 235/100,000 (6-11 months), 203/100,000 (12-23 months). In addition, it was estimated that 17-28% of community-acquired pneumonia among young children are due to pneumococcus.

The pneumococcal vaccine currently available in Hong Kong is a 23-valent polysaccharide vaccine. Since polysaccharides can only stimulate mature B cells but not T cells, this vaccine is not immunogenic for children under 2 years of age. Therefore it has limited use in older children with high risk for invasive pneumococcal infection: sickle cell disease, chronic underlying disease, HIV infection, immunocompromised, before splenectomy. The newer conjugate pneumococcal vaccine is a heptavalent conjugated pneumococcal containing serotypes 4, 6B, 9V, 14, 18C, 19F and 23F conjugated to a nontoxic mutant diphtheria toxin CRM197. In a large population-based study of 37,868 children in Northern California, this vaccine was found to be efficacious in reducing bacteremia and pneumonia.1,2

This vaccine was licensed in February 2000 in the US and currently given routinely to normal children at 2, 4, 6, 12-15 months of age there. An additional dose of the 23-valent polysaccharide vaccine is advocated at 24-59 m for children belonging to the high risk groups. The protective efficacy of this vaccine against invasive pneumococcal disease was 97.4% (fully vaccinated analysis, against serotypes included in the vaccine), 93.9% (intent-to-treat analysis, against serotypes included in the vaccine) and 89.1% against all serotypes. The protective efficacy against clinical pneumonia with a positive chest X-ray was 32% in children under 12 months of age and 23% in those under 24 months of age. The vaccine was also efficacious in low birth weight and preterm infants. It was found to be 100% effective against invasive disease of vaccine serotypes in 1756 children with birth weight <2500 gm and in 4340 preterm infants.

There are other conjugate pneumococcal vaccine being developed: a 9-valent vaccine, which contains serotypes 3 and 7V in addition to the seven in the heptavalent vaccine, and an 11-valent vaccine, which contains serotypes 1, 5 in addition to those included in the 9-valent vaccine. A recent study showed that serotypes 6B, 19F, 23F and 14 were the most common serotypes amongst the isolates from 383 nasopharyngeal swabs, 140 mucosal clinical specimens and 200 blood and cerebrospinal fluid samples.3,4 The 7-valent vaccine would provide close to 90% of isolates that caused invasive disease in young children in that study. However, whether the conjugate pneumococcal vaccine should be routinely used is Hong Kong is still uncertain. There is a lack of documentation of pneumococcal disease burden in Hong Kong. There are very few laboratory-diagnosed bacteremia or meningitis in Hospital Authority hospitals and the difficulty in documenting pneumococcal pneumonia in children is a problem shared worldwide. Better definition of the disease burden of Strep. Pneumoniae will help guide rational policy-making regarding the use of the vaccine.

Despite the severity of pneumococcal pneumonia, the majority of respiratory infections in children have a viral etiology. In Queen Mary Hospital, 2001 to 2002, 60% of the children admitted with an acute respiratory infection had a virus detected in their nasopharyngeal aspirate, either by immunofluorescence testing or PCR. The viruses were: Influenza A & B (7.3%), respiratory syncytial virus (RSV) (6.9%), parainfluenza 1-4 (5.9%), adenovirus (4.9%) and rhinovirus (35%).5 Influenza is recognized to cause complications and mortality in people with certain underlying conditions but recently, also shown to cause increased hospitalization in otherwise normal young children.6,7 In the US, the rates of annual excess hospitalization for cardiopulmonary conditions in children without underlying conditions were: 104/10,000 (<6 m), 50/10,000 (6-<12 m), 19/10,000 (12-36 m), 9/10,000 (3-<5 y) and 4/10,000 (5-<15 y). It also accounted for 6-15 outpatient visits/100 children and 3-9 courses of antibiotics/100 children. In Hong Kong, a population-based study showed that the rates of hospitalization associated with influenza were as high, if not higher than that reported in the US. The influenza-related excess hospitalization rates (per 10,000 population) for acute respiratory disease in 1998 and 1999 respectively, were 278.5 and 288.2 for children aged 0 to <12 months, 218.4 and 209.3 for those aged 1 to <2 years, 125.6 and 77.3 for those aged 2 to <5 years, 57.3 and 20.9 for 5 to <10 years old and 16.4 and 8.1 for those aged 10 to 15 years.8

Influenza is the only respiratory virus that has a licensed vaccine for prevention of disease. Currently, an inactivated trivalent influenza vaccine is available for use, with an efficacy of 70-80% (50-95% depending on match of strains). This vaccine requires annual vaccination for strain variation and the short duration of protection. In the US, this vaccine is recommended for persons with asthma or other chronic lung disease, hemodynamically significant cardiac disease, immuno-suppression, HIV infection, hemoglobinopathies, taking long term aspirin, chronic renal dysfunction, chronic metabolic disease including DM, persons ³50 years of age and healthcare workers. In light of the recent data on high morbidity in healthy young children, the Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) encouraged vaccination of all children 6 months through 23 months when feasible as well as the household contacts and caretakers of children <2 y for the 03-04 season in the US. In Hong Kong, the Department of Health recommended this vaccine for residents of nursing home and the Hospital Authority recommended it for children with congenital heart disease, chronic lung disease but excluding asthma, hospitalized children on aspirin, psychogeriatric inpatients and institutionalized mental handicapped patients.

The existing inactivated influenza vaccine is less than ideal. It has to be given via the intramuscular route annually. There is a new live attenuated intranasal influenza vaccine that will soon be available. This is a trivalent (2A/1B), live attenuated cold adapted vaccine that is safe even in children with moderate to severe asthma. No injection is needed since it is given via the intranasal route. It is capable of inducing a broad immune response that includes cellular and mucosal immunity as well as generating influenza specific antibodies). The efficacy of this vaccine was 93% against culture-confirmed influenza and even showed a high degree (86%) of protection against a mismatched variant in the second year.9

Other viruses that cause significant disease in children include RSV and parainfluenza virus. It is estimated that the incidence of RSV associated lower respiratory tract infection to be 3-12/100 children in the first year of life in the US. Conditions associated with increased severity of RSV disease: prematurity, BPD or CLD of prematurity and congenital heart disease. RSV has 2 major antigenic subgroups: RSV/A and RSV/B viruses. RSV/A accounts for majority, severe disease but both subgroups co-circulates at the same time. The antigenic diversity is primarily based on the G (attachment) glycoprotein while the F (fusion) glycoprotein is conserved within subgroups. Both surface glycoproteins are capable of inducing virus-specific serum neutralizing antibody responses. Since natural RSV infection induces incomplete protection but reduces the frequency of severe infection with re-infection, it may be more realistic to have similar expectations from an RSV vaccine. The goals for an RSV vaccine therefore include prevention of death and hospitalization, prevention of lower respiratory tract infection, reduction of complications, for example, otitis media, and reduction of antibiotic use. The initial inactivated RSV vaccine was developed in the 1960s but was found to cause more severe disease in children infected with RSV in the subsequent season and abandoned. Since then, intensive research during the past two decades has resulted in several candidate vaccines. These include subunit vaccines and cold-passaged/temperature-sensitive mutant vaccines. Some of these vaccines have undergone testing in humans.10

Parainfluenza virus also causes of upper respiratory tract infection, croup, pneumonia and bronchiolitis in infants and children. Parainfluenza type 3 is only second to RSV in causing lower respiratory tract infection in infants and the second leading cause of bronchiolitis and pneumonia in infants under 6 months of age in the US. Live attenuated parainfluenza vaccines from both human and bovine strains have also been developed. The live-attenuated bovine vaccine is administered via the intranasal route. It has undergone phase I and II trials given to infants at 2, 4, 6 and 12 to 15 months of age.

Maternal immunization is another approach that is being explored to provide protection against infections for young infants. Transplacental transfer of IgG, especially IgG1, happens mostly in the last 4-6 weeks of gestation leading to concentrations of antibodies that can be higher in the term newborn than in the mother. Infants born with high antibody concentration resulting from immunization of their mothers could be protected while their immune system matures to respond adequately to vaccines. Vaccines under consideration for maternal immunization include vaccines against RSV, parainfluenza, influenza and Strep pneumoniae.

Considerations for Hong Kong in the near future will include the rational and appropriate usage of the conjugate pneumococcal vaccine, if and when it is licensed here, and that of the current and the upcoming live-attenuated influenza vaccine. Further into the future will see the development and availability of the RSV and parainfluenza vaccines.

References

  1. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000;19:187-95.
  2. Black SB, Shinefield HR, Ling S, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J 2002;21:810-5
  3. Chiu SS, Ho PL, Chow FK, Yuen KY, Lau YL. Nasopharyngeal carriage of antimicrobial-resistant Streptococcus pneumoniae among young children attending 79 kindergartens and day care centers in Hong Kong. Antimicrob Agents Chemother 2001;45:2765-70.
  4. Ho PL, Chiu SS. Serotypes of nasopharyngeal and clinical isolates of Streptococcus pneumonia: a high correlation with the heptavalent conjugate pneumococcal vaccine (manuscript in preparation)
  5. Tang WH, Peiris JSM. (unpublished data)
  6. Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med 2000;342:232-9.
  7. Neuzil KM, Mellen BG, Wright PF, Mitchel EF Jr, Griffin MR. The effect of influenza hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;342:225-31.
  8. Chiu SS, Lau YL, Chan KH, Wong WH, Peiris JS. Influenza-related hospitalizations among children in Hong Kong. N Eng J Med 2002;347:2097-103.
  9. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Eng J Med 1998;338:1405-12.
  10. Kneyber MC, Kimpen JL. Current concepts on active immunization against respiratory syncytial virus for infants and young children. Pediatr Infect Dis J 2002;21:685-96.

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