Pneumococcal conjugate vaccines as a probe for better understanding
pneumococcal respiratory infections
Ron Dagan
Pediatric Infectious Disease Unit, Soroka University Medical Center and the
Faculty of Health Sciences, Ben-Gurion University of the Negev,
Beer-Sheva, Israel
Respiratory infections are the leading cause of morbidity and mortality in young infants
and young children globally. Streptococcus pneumoniae (Pnc) is the leading bacterial
pathogen in respiratory infections and a major cause of deaths in children <5 years of age
(~ 11% of all deaths in this age group [1]). Around 14.5 million episodes of serious
pneumococcal disease occurred in the year 2000 in children <5 years with ~ 825,000
estimated deaths, due to serious pneumococcal disease. 95% of these serious
pneumococcal disease cases and mortality were attributed to pneumonia.[1] Most serious
diseases caused by pneumococcal respiratory disease occur in only 10 countries in Africa
and Asia, but pneumococcal respiratory infections are a serious problem globally.[1]
Thus it is clear that preventing pneumococcal severe respiratory infections is one of the
main global goals.[2] However, what is pneumococcal respiratory disease? The tradition
wisdom that pneumococcal pneumonia presenting as alveolar (or lobar) pneumonia is
shown to be wrong, although this entity is definitely enriched with bacterial pathogens in
general and Pnc in particular.
1
Using any diagnostics tools detects a bacterial pathogen in only a low proportion
of LRI and pneumonia. On the other hand, series of efficacy studies with pneumococcal
conjugate vaccine in the US, South Africa, the Gambia and the Philippines showed that
the use of pneumococcal conjugate vaccines (PCVs) reduced alveolar pneumonia by
~33%, pointing clearly to an important role of Pnc in alveolar pneumonia.[3] However,
other endpoints, such as any severe pneumonia (efficacy of 21%) and any clinical
pneumonia (efficacy of 8%) were all affected by PCVs, suggesting that Pnc has a role
even in the less “classical” pneumonia. Furthermore, the less specific entities were far
more common than the classical alveolar pneumonia endpoint, thus a smaller percentage
of efficacy in the “non-specific” pneumococcal cases led to a much higher vaccine
attributable reduction (VAR) of disease. Thus, for each episode of culture-proven
pneumococcal pneumonia, 7 radiologically-proven pneumococcal pneumonia episodes
and 19 “clinical pneumonia” episodes could be prevented. [3]
Even more surprising findings were that PCVs could reduce what was considered
until recently as “pure” viral infections. The first work was from Israel, where a PCV
could reduce 20% of bronchiolitis episodes in daycare center toddlers attendees.[4]
Later, in a series of studies, Madhi and Klugman showed in South Africa that
hospitalization due to virus-positive pneumonia including RSV, human
metapneumovirus, parainfluenza 1-3 and influenza A and B, were significantly reduced
by a PCV.[5] This was the proof of the concept that viral infections often represent in
fact a common viral-bacterial co-infection was proven. By reducing the pneumococcal
component, severity of the viral infections can be reduced, resulting in a significant
reduction in the proportion of the children ending up being hospitalized.
2
After the introduction of the 7-valent PCV (PCV7) to various countries, a
reduction in overall outcomes in respiratory infections could be observed. In the US,
<30% of hospitalizations due to all-cause pneumonia was seen in the post PCV7 in
children <2 years of age. However, at the same time, a 20% reduction of hospitalization
due to non-pneumonia LRIs was seen[6] showing that for each case of invasive
pneumococcal disease prevented, hospitalization of 14 cases of respiratory infections was
prevented by PCV7.
The series of studies reviewed above contributed on the one hand to our
understanding of the role of pneumocococci in respiratory tract infections, but on the
other hand showed that the use of PCV was associated with much greater than expected
reduction in respiratory disease. The insights acquired on pneumococcal role in the
overall respiratory disease burden and the insights acquired on the PCV role in the
reduction of such disease lead to the term “vaccine probe” which means that the use of
vaccine can show us its unexpected benefit and teach us about pathogens and
epidemiology.
We also learned that some serotypes not included in the PCV7 are important,
especially for the complicated (or complex) pneumonia, namely pleuropneumonia (or
empyema). The most important serotypes are 1, 3, 5, 7F, 14 and 19A, of which only
serotype 14 is included in the PCV7. Thus, no one should be surprised that empyema
was not reduced after the introduction of PCV7, especially given the fact that another
non-Pnc pathogen responsible for this complex entity was MRSA. In fact, an increase in
this entity was observed worldwide regardless of PCV7 administration. On the other
hand, the new generation PCV10 and PCV13 vaccines contain the “empyema serotypes”
3
and thus after switching from PCV7 to PCV13, we are expecting reduction of empyema.
However, the effectiveness of the new PCVs has still to be proven, following vaccine
implementation.
In summary, the vaccine probe studies has taught us how important PCVs are and
that the widespread use of these vaccines can reduce mortality and morbidity. Much
more can be learned if additional high quality surveillance programs are set up in
countries adopting the vaccine.
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REFERENCES
1. O'Brien KL, Wolfson LJ, Watt JP, et al. Burden of disease caused by Streptococcus
pneumoniae in children younger than 5 years: global estimates. Lancet
2009;374:893-902.
2. World Health Organization. Pneumococcal conjugate vaccine for childhood
immunization - WHO position paper. Weekly Epidemiological Record. No. 12,
2007, 82, 93-104 (www.who.int/wer).
3. Madhi SA, Kuwanda L, Cutland C,Klugman KP. The impact of a 9-valent
pneumococcal conjugate vaccine on the public health burden of pneumonia in HIVinfected and -uninfected children. Clin Infect Dis 2005;40:1511-8.
4. Dagan R, Sikuler-Cohen M, Zamir O, Janco J, Givon-Lavi N,Fraser D. Effect of a
conjugate pneumococcal vaccine on the occurrence of respiratory infections and
antibiotic use in day-care center attendees. Pediatr Infect Dis J 2001;20:951-8.
5. Madhi SA, Klugman KP. Efficacy and Safety of Conjugate Pneumococcal Vaccine in
the Prevention of Pneumonia (Chap. 22). In: Siber GR, Klugman PK, Makela H, eds.
Pneumococcal Vaccines: The impact of Conjugate Vaccine. Washington, DC, ASM
Press, 2008:327-346,
6. CDC. Pneumonia hospitalizations among young children before and after introduction
of pneumococcal conjugate vaccine - United States, 1997-2006. MMWR 2009;6:14
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