Vaccination and the respiratory tract - what should we know?

Vacinas e o trato respiratório - o que devemos saber?
Calil Kairalla Farhat, Otávio Augusto Leite Cintra, Miguel W. Tregnaghi
J Pediatr (Rio J) 2002;78(Suppl.2):s195-s204

Introduction

The importance of viral and bacterial infections that affect the lower and upper airways is well known by all of us. These are the types of infection that most often affect humans. Two are the recommendations for the treatment of acute respiratory infections (ARI): antimicrobials (as therapeutic measure) and immunization (as prophylaxis).

The use of antimicrobials has not involved many criteria and is often inadequate and abusive, thus favoring the growth and further development of bacterial resistance to antibiotics. As far as prophylaxis is concerned, vaccines play a key role in the fight against infections and their complications. This is what occurred with the vaccines against diphtheria, pertussis and measles, among others.

Until the early 1970s, in the previous century, measles used to be one of the major causes of death among children aged less than five years. This occurred especially due to the respiratory complications of the viral infection and due to a synergistic relationship between the measles virus and malnutrition, which used to affect Brazilian children more frequently. Nowadays, thanks to the National Immunization Program (PNI - Programa Nacional de Imunização), we have diseases such as measles, diphtheria, pertussis, among others, under control.

The new use of old vaccines and the use of new vaccines have extended the spectrum of control over infections, especially ARI.

After historical notoriety due to the tragic pandemic of influenza in 1918-1919, the influenza virus has maintained its importance universally, and has constantly been a reason for concern for the World Health Organization (WHO). Actually, it is the only respiratory virus against which a vaccine was developed. The vaccine contains inactive viruses (either whole or fragmented) and consists of two strains of the influenza virus (A and B). (1) The composition is determined by the prevalence of circulating viruses in the community.

The use of the influenza vaccine is usually indicated during the fall and is applied once a year, after the age of six, in people with increased risk of complications caused by influenza-related infections, (1) in those who may transmit the virus to those at higher risk, as is the case of health professionals, (6,16,17) in elderly people over 65 years, in industrial and commercial workers, or group workers. (5,15) The vaccine has proved useful for the protection against the disease and in the reduction of mortality, hospital admissions, pulmonary complications and otitis media. (7,10) Two important trends should be considered: vaccination of healthy children, between the ages of six and 23 months, (7,10,11) and vaccination of healthy children and adolescents, if desired. (1,8)

Haemophilus influenzae is an important etiologic agent, causing meningitis, pneumonia, acute otitis media, sinusitis, and epiglottitis, and usually affecting children younger than five years. The capsulated strains of the bacteria include several types (a through f), but type b is the most important. H. influenzae type b (Hib) is present in almost all the invasive infections provoked by this bacterium. On the other hand, the non-capsulated, non-typeable strains are mainly involved in the etiology of otitis media, sinusitis and pneumonias.

The anti-Hib conjugate vaccines were included in the vaccination calendar of the National Immunization Program in 1999, and have already shown to remarkably reduce the number of cases of meningitis related to this agent. Countries with adequate vaccine coverage, such as France, Finland and Uruguay, among others, have practically eradicated Hib meningitis.

There are no national data that could show the impact of vaccination on respiratory diseases; however, some literature data indicate a remarkable reduction in the cases of epiglottitis (9,14) and pneumonia. (12,14)

The respiratory syncytial virus (RSV) is extremely important, as it is the major cause of bronchiolitis and pneumonia in infants. No vaccine against RSV has been available so far, and the infection may be prevented with specific human immunoglobulin or with humanized monoclonal antibodies (palivizumab), as recommended by the American Academy of Pediatrics. (2)

Streptococcus pneumoniae (pneumococcus), with approximately 90 serotypes identified, is one of the major bacteria that affect human beings and is responsible for a large part of community-acquired infections, pneumonia, otitis media, sinusitis, meningitis, peritonitis and arthritis. For the prevention of pneumococcal infections, there is a vaccine containing capsular polysaccharide of 23 pneumococcal serotypes, which account for the majority of cases involving humans. This 23-valent vaccine is restrictively indicated to risk groups with a propensity for pneumococcal infection and to those who acquire the infection and have great chances to present with a more severe status. This vaccine may only be used after the age of two, since it is ineffective in younger children, who are at higher risk of severe and more frequent pneumococcal infection.

Quite recently, a heptavalent pneumococcal conjugate vaccine has been approved for use after the second month of life. (3) This new vaccine has proved very useful in the prevention of invasive disease and pneumonia, and has shown to have some effect on otitis media and its consequences. (3,13) The heptavalent vaccine allows a coverage of 63.5% in our environment, and of 90% for penicillin-resistant serotypes. The 9-valent vaccine, still under study, contains the seven serotypes of the heptavalent vaccine plus serotypes 1 and 5, which are very frequent in our patient population. The use of this vaccine would cover approximately 80% of the cases. (4)

There have been hope and expectations for the development of new vaccines that are still under study and some which are about to be released. Soon, there may be new vaccines against influenza, pneumococci, and RSV, which will certainly bring a lot of advantage to the fight against respiratory infections.

Immunization against Haemophilus influenzae, influenza and RSV

ARIs are the major cause of morbidity and mortality worldwide. (18) According to WHO data, a total of four million deaths are estimated to occur every year due to ARI in developing countries, which means approximately one death every seven seconds of children younger than five years. (19) Since 1987, WHO has put in a great deal of effort to control ARIs through community-based programs, epidemiological surveillance and encouragement of vaccination as a prevention measure, following the example of the measles vaccination and its impact on the reduction of infant mortality. (20)

Viruses and bacteria are the most important etiologic agents of ARIs; the viruses are more frequent while bacteria are associated with higher mortality. (21) Various epidemiological studies of the etiology of ARIs have been carried out worldwide and have revealed that the same etiologic agents are present in industrialized and developing countries, with a significantly higher mortality rate in developing countries. (22) Within this context, the universal implementation of preventive measures by means of vaccination should be considered. (23)

The prevention of respiratory diseases by immunization is one of the main measures for the control of ARIs, given its high efficiency. (23) The impact of vaccination on the prevention of respiratory diseases caused by Haemophilus influenzae, influenza virus and RSV will be discussed next.

Anti-Haemophilus influenzae vaccine

H. influenzae is a gram-negative coccobacillus that is often found in the respiratory tract flora of humans. Its capsulated forms, especially H. influenzae type b (Hib), can cause invasive diseases, such as meningitis, bacteremia, pneumonia, arthritis, epiglottitis, among others. (24) In industrialized countries, Hib is the major etiology of meningitis. (25) In developing countries, as occurs in the African continent, infections caused by Hib have a remarkable impact on the etiology of ARIs, accounting for 20% of pneumonias in children in Gambia. (26)

Pneumonia caused by Hib is associated with high morbidity and mortality, and is more frequent in the first year of life. (26) Epiglottitis, also caused by Hib, often occurs in children aged three to four years, and requires advanced management of airways in all cases. (27)

H. influenzae is also the etiologic agent of ARIs of the upper respiratory tract and is one of the major agents of acute otitis media (AOM). It may also be associated with pneumonias, but with a different clinical status and evolution from that observed in pneumonias caused by Hib. (28) Even after the vaccination has been implemented, the incidence of H. influenzae (except type b) remains low, although a relative increase in its frequency has been reported, comparatively to that observed for Hib. (29)

Since a conjugate vaccine against Hib was developed, the epidemiology of this infection has changed. Its first significant impact was reported in Finland, where the incidence of Hib meningitis was high. (30) This fact is known on a worldwide basis as Finland effect and was later observed in all the countries in which the vaccination against Hib had been implemented. (31)

The impact of the vaccination against Hib on ARIs may be assessed by the reduction of cases of pneumonia and epiglottitis. (32) Many pneumonias may be caused by H. influenzae different from type b, against which vaccination would produce no effect. (29) In addition, the differences in the epidemiology of Hib between industrialized and developing countries may mean a more significant impact of the vaccination against Hib on ARIs in developing countries. (32)

The worldwide incidence of invasive diseases caused by Hib in the period before the implementation of the vaccine was 71/100,000, totaling 445,000 cases a year, with 108,500 deaths. If pneumonias without bacteremia are included, these figures rise to 2.2 million, with approximately 520,000 deaths. (31) The impact of vaccination against Hib would be evident in the reduction of these figures; however, it is estimated that only 38,000 deaths are prevented a year due to the restricted use of the vaccine by industrialized countries and by some developing countries. (23,31)

In a study conducted by Mulholland et al. (33) in Gambia, the incidence of Hib as cause of pneumonia was assessed in a controlled study of the impact of vaccination against Hib. These authors have observed a 100% reduction of the cases of pneumonia caused by Hib in children that had received the vaccine, with bacteriological confirmation, and 21.1% of the cases only by means of radiological confirmation.

Levine et al. (34) have evaluated the impact of vaccination against Hib and the occurrence of pneumonia in Chilean children. These authors have shown a fivefold reduction in the cases of pneumonia without bacteremia with the use of vaccination, with a 26% protection from any type of pneumonia, and 22% for those with alveolar consolidation or pleural effusion.

Garpenholt et al. (35) have reported a reduction in the occurrence of epiglottitis in Swedish children. In the period before vaccination, the incidence of epiglottitis was 20.9/100,000/year, with a drop to 0.9/100,000/year after 10 years of regular immunization against Hib.

This way, the vaccination against Hib is an important step in the reduction of severe ARIs that affect the lower respiratory tract. This shows the impact of preventive measures by means of vaccination for the control of ARIs and consolidates this action as an effective measure, as observed in the measles vaccination. The Pan-American Health Organization (PAHO) and WHO should devote some effort to make the vaccine against Hib available in all continents, especially in developing countries.

In Brazil, the vaccination against Hib has been carried out on a regular basis since 1999, as part of the National Immunization Program. There has been a marked reduction in the cases of invasive diseases caused by Hib, assessed mainly by the reduction in the cases of meningitis. The reduction in the cases of pneumonia has not been well assessed yet.

The prevention of respiratory diseases by means of vaccination is important for all children and also for high-risk patients. Patients who were submitted to splenectomy or who have congenital or acquired immunodeficiencies might require new doses of anti-Hib vaccine, which can be applied every five years.(36)

Vaccine against the influenza virus

The influenza virus is a capsulated virus with segmented, single-stranded RNA genome, which consists of two superficial proteins called hemagglutinin and neuraminidase, involved in the physiopathology of the disease and in the host's immune response. (37) Thanks to the characteristics of its segmented RNA, this virus can suffer minor and major antigenic variations, which determine its annual occurrence, with well-defined epidemic characteristics, and possible global dissemination in pandemics. (37)

The influenza virus epidemic is associated with the increase in morbidity and mortality, as well as with the great number of cases of pneumonia and hospital admissions. (38) This is well-known in elderly people over 60 years (39) and in populations at risk for severe influenza infection, characterized by patients with cardiopulmonary diseases (40) and immunocompromised patients (41). Aside from these populations, other ones have been regarded as having higher risk for complications and hospital admissions in influenza epidemics (for instance, pregnant women and patients with metabolic diseases). (42)

Recently, the impact of the infection caused by the influenza virus in children has been better assessed. Neuzil et al. (43) have found a higher rate of hospital admission due to cardiopulmonary problems in infants younger than 12 months during epidemics of influenza. The rates of hospital admission were inversely related to age, and were 50/10,000 in infants between six to 12 months, and 4/10,000 for children between five and 15 years. In addition, these authors have observed a 10 to 30% increase in the use of antibiotics during influenza epidemics for the treatment of influenza-related complications, especially sinusitis and pneumonia.

Izurieta et al. (44) have also found a higher rate of hospital admission due to respiratory disease in young children during the epidemic of influenza. These authors have found 193 to 231/100,000 hospitalized people/month among children aged less than two years. The values observed were approximately 12 times higher than those observed in high-risk children and was similar to that calculated for children between five and 17 years who are at risk.

Thus, children younger than one year may be regarded as a population at risk for more severe influenza infection and are therefore considered for the use of preventive measures. (43)

The vaccine against influenza consists of inactive viruses, which can be whole or fragmented. It contains three strains of the influenza virus, two of influenza A (characterized by H1N1 and H3N2), and one of influenza B. The vaccine is produced annually according to WHO recommendations. Currently, there is a specific recommendation for the north hemisphere and another one for the southern hemisphere. (45) The efficiency of the vaccine against influenza ranges from 70 to 90% for the prevention of infection by this virus; however, the main impact of vaccination can be assessed by the reduction of morbidity due to influenza in healthy populations and in those at risk. (46)

The vaccination against influenza reduces the rates of hospital admissions in vaccinated elderly people. (47) This results mainly from the reduction in the number of cases of pneumonia in this high-risk population. (46) This can also be observed in patients with chronic pulmonary diseases who were vaccinated against influenza. (40) The current recommendation for the vaccination of populations against influenza includes pregnant women, patients with cardiopulmonary diseases (including respiratory allergy), immunocompromised patients, health professionals and those who take care of risk populations. (42)

The vaccination against influenza has also been assessed as to its efficiency in reducing the episodes of acute otitis media in children. Both the inactivated vaccine8 and the vaccine containing attenuated viruses, still unlicensed, have proved effective in reducing AOM in vaccinated patients. (48)

The vaccination against the influenza virus is an efficient measure and produces a great epidemiological impact on the reduction of respiratory diseases, either caused by influenza or by its complications. These facts have also been reported in risk populations; however, recent data have shown larger benefits of the immunization against influenza, and the current discussion on this topic is focused on the use of a universal vaccination against this agent.

Passive immunization against the respiratory syncytial virus (RSV)

The RSV is the major agent of ARI, which affects the lower respiratory tract of children younger than one year and is the most frequent agent of pneumonia and bronchiolitis in infants. (49) The RSV is a capsulated virus, with a single-stranded RNA genome, which contains two surface glycoproteins, called fusion (F) and adsorption (G). These glycoproteins are related to the infection ability of the virus and to the host's immune response. (50) There are two major groups of RSV, A and B, with several subgroups.

The RSV is typically seasonal, occurring in the fall and winter months in countries with temperate climate. (51) These characteristics have also been observed in Brazil, in the cities of Rio de Janeiro (52), São Paulo (53) and Ribeirão Preto (54), where the epidemic period of RSV occurs in the first half of the year, with variations in peak months, depending on the city.

The epidemiology of RSV is well known. (51) The frequency of RSV infection reaches up to 70% in the first year of life, and nearly all the children older than two years have already come into contact with this virus. (55) Approximately 30 to 40% of primary RSV infections affect the lower respiratory tract, with the hospitalization of one in every 100 infected children, (56) totaling 90,000 hospital admissions/year in the United States, which represents about 0.5% to 3.2% of hospital admissions in that country. (57) Reinfection by RSV is frequent; however, the subsequent episodes are usually less severe. (55)

The major risk factors for higher severity of RSV infection are prematurity, cardiopulmonary diseases and immunosuppression. (58) In these patients, the risk of RSV affecting the lower respiratory tract is high, with deterioration of the health status and hospitalization, sometimes in intensive care units (ICU). In certain patients, mortality may be quite high, as observed in patients submitted to bone marrow transplant, in whom RSV-related death may account for as much as 80%. (59) Other risk factors have been associated with higher severity of RSV infection, such as exposure to tobacco smoke, early weaning, presence of twin pregnancy, age less than six months, presence of siblings in day care centers or in school, low socioeconomic status, black people, and males; however, these factors are less significant than those previously mentioned. (58)

The prevention of RSV infection is a priority for the development of vaccines. (23) Nevertheless, the experiment with an RSV vaccine inactivated by formalin (60) in the 1960s delayed the development of a vaccine against this agent, since further knowledge about its physiopathology was necessary. Nowadays, there are at least two vaccines being clinically tested; however, the results have not allowed for its large-scale production. (61)

The humoral immune response against RSV has been associated with the protection of infants (56) and adults, (62) with lower incidence of the disease in the lower respiratory tract. Since then, attempts to prevent RSV infection by passive immunization have been made with standard IV immunoglobulin, specific immunoglobulin and, recently, humanized monoclonal antibodies.

The Prevent Study Group carried out with IV human immunoglobulin, specific to RSV (RSV-IVIG), has shown an average reduction of 41% in the hospitalization rate of preterm infants, with variations according to gestational age and presence of chronic lung disease. (63) The humanized monoclonal antibody, called palivizumab, has also proved efficient in reducing admissions of preterm infants to hospital and ICUs, with rates of 55% and 57%, respectively, in a multicenter, randomized, placebo-controlled study (Impact-RSV Study Group). (65) Differences as to the reduction in hospitalization rates have also been observed with palivizumab, taking gestational age and presence of chronic lung disease into consideration. Based on these studies, the American Academy of Pediatrics recommended the prevention of RSV with passive immunization in 1999, preferably with the use of palivizumab, since it is easier to administer and is not a blood derivative, among other characteristics. (65)

The prevention of RSV with palivizumab should be made by means of monthly intramuscular injections in the dose of 15mg/kg, throughout the epidemic period of the virus. This involves elevated costs and, therefore, the prevention is indicated for preterm infants at higher risk of severe infection. The following groups of patients were stratified for the administration of palivizumab, according to the American Academy of Pediatrics: (65)

- children younger than two years with chronic lung disease who required medical treatment up to six months before the RSV season;

- infants with 32 weeks gestational age or less, with or without chronic lung disease. For infants with 29-32 gestational weeks, the prophylaxis is recommended up to the sixth month of life, and for those with less than 29 gestational weeks, the prophylaxis should be extended to infants up to the 12th month of life;

- for infants with 32 to 35 gestational weeks, palivizumab should be indicated according to the presence of additional risk factors, as those mentioned herein. This occurs due to the great number of infants included in this range of gestational age, which results in unfavorable cost-effectiveness.

For other patients, such as those with heart diseases and immunodeficiencies, or for the control of hospital outbreaks, the prophylaxis with palivizumab may bring some benefits; however, there are no controlled studies for this group of patients. For infants with cyanotic congenital heart disease, the use of RSV-IVIG was associated with worse postoperative prognosis, attributed to blood viscosity; this should not be expected from palivizumab. Infants with heart diseases without relevant hemodynamic repercussion may receive prophylaxis with palivizumab.

The post-marketing studies of palivizumab have shown a higher efficiency than that observed in clinical trials. (66) However, the discussion about palivizumab focuses on the cost/benefit ratio, due to the elevated cost of prophylaxis caused by the monthly administration of the drug. There are several pharmacoeconomic studies of the prevention of respiratory syncytial virus; (67,68) however, the studies rely on the frequency of hospital readmissions of preterm infants after discharge from the nursery/ICU, moment at which variations between 5 and 40% can be observed. (69) In a survey carried out in Ribeirão Preto, the rate of hospital readmissions of preterm infants was 16%, considering only the admissions to the Hospital das Clínicas (CINTRA, unpublished data). This way, the use of palivizumab should be based on the previous indications, on the epidemiological characteristics of each city and on the individual analysis of each case, in addition to the ethical implications that might result from the lack of indication or lack of discussion on the use of prophylaxis with the parents of the patients.

Immunization against Streptococcus pneumoniae

Respiratory infections comprise a large number of clinical manifestations, with several etiologies and variable severity. These infections have affected men since time immemorial. There is evidence of respiratory infection in Egyptian mummies, aged between 1,250 and 1,000 years BC, but the first descriptions and therapeutic indications were made by Hippocrates. In the 19th century, the first advances in the clinical and pathoanatomical aspects were made with regard to the identification of the first etiologic agents, but only during the last century, important events changed the prognosis of many of these infections. (70) Perhaps the most relevant event in the last few years has been the development of antimicrobials; this aroused such enthusiasm that it was believed that the treatment of any respiratory infection would be possible in a short period of time; however, this initial feeling did not last long. Soon came the first therapeutic failures. There were a large number of etiologic agents that were not covered by the spectrum of the available antibiotics and, in addition, in a short time, the first resistant bacteria appeared. From that time up to now, the growing number of new antibiotic drugs has not been able to follow the increasing resistance of most bacteria to antibiotic therapy.

The severity of several diseases, which in some situations might compromise the airways, has drawn our attention to prevention many years before the advent of antimicrobials. Jenner developed the vaccine against smallpox at the end of the 18th century, and the vaccines against diphtheria and pertussis appeared in the 20th century's first decades, and during the 1940s, the first successful attempts to produce a pneumococcal vaccine, which included five serotypes, were made. (71) Although this vaccine was not used at the beginning, it became important three decades thereafter, when 14 serotypes were added.

Over time, these vaccines showed to be useful in the prevention of infections. Other vaccines, such as those against measles, chickenpox, influenza and pneumococci (23 serotypes), were developed, covering diseases capable of causing severe and variable respiratory tract infections. In the last few years, new vaccines, targeted at the age group in which respiratory infections are more prevalent and severe, have been developed: (72,73) anti-Haemophilus influenza b and pneumococcal conjugate vaccines. The former one, as previously mentioned, has been used for over one decade, (74) and has been included in the official vaccination programs in several countries around the world, especially in the American continent. The study of this vaccine has been important to the production of polysaccharide vaccines. Separately, these vaccines are immunogenically poor before the age of two years, especially in small infants, since these produce a t-independent immunogenic response, basically mediated by IgM. When the polysaccharide is conjugated with a carrier protein, the immune response is changed to a t dependent response, mediated by IgG, which is remarkably efficient from the first weeks of life. (75) Today, the following vaccines have been used: Hib polysaccharide (PRP) conjugated with distinct carrier proteins, tetanus toxoid (T), diphtheria toxoid (D), outer membrane protein of meningococcus group b (OMP) and a nontoxic mutant of the diphtheria toxin (CRM197). All of the anti-Hib conjugate vaccines have a great impact on the reduction of the forms of presentation of the disease, but are also responsible for a decrease in the forms of the pharyngeal carrier. (76) The efficiency of anti-Hib vaccines has encouraged several researchers to try to conjugate various polysaccharides of different agents, such as Streptococcus pneumoniae, Neisseria meningitidis and Staphylococcus aureus.

Antipneumococcal vaccines

The infections caused by S. pneumoniae are extremely frequent in community-acquired infections. S. pneumoniae is responsible for a wide series of manifestations and is the main etiologic agent of pneumonias, bacterial meningitis (outside epidemic outbreaks of meningococcal infections), acute otitis media, and occult bacteremia. Aside from these infections, this agent might be involved in peritonitis, abscesses, arthritis, etc. Every year, 1,200,000 deaths are caused by pneumococcal pneumonia in children younger than five years. In developing countries, between 100,000 and 500,000 deaths that occur every year, secondary to meningitis, are caused by S. pneumoniae. Moreover, pneumococcal infections, due to their frequency, incur high health costs. (72,73,77) Another relevant aspect is the increasing resistance to regularly prescribed antibiotics, which requires the use of other therapeutic schemes, which, in their turn, increase health expenses. (78-80) This has shown that vaccines are more and more necessary for the prevention of such infections. This applies to antipneumococcal vaccines developed in the last century, initially with five serotypes, then with 24, and in the 1960s and 1980s, with 23 serotypes.

The latter, only with capsular polysaccharides, has been regularly used in individuals older than 65 years, or from the second year of life onwards, when associated with the predisposing situation for acquisition of S. pneumoniae. Among these infections we have chronic respiratory or cardiovascular diseases, functional or anatomical asplenia, sickle-cell anemia, nephrotic syndrome, chronic renal insufficiency, Hodgkin's disease, or any other immunosuppressive situation (transplanted patients, chemotherapy, HIV), in addition to population groups that live in closed communities(72,82-86) (Table 1).

Table 1 -
Recommendation of antipneumococcal vaccines with 23 serum types for children older than two years

Pneumococcal conjugate vaccines

The inconvenience of using the available polysaccharide vaccines in children younger than two years, age at which pneumococcal disease is highly prevalent, has led to the development of new antipneumococcal vaccines. Currently, with the results obtained from the anti-Hib vaccine, the polysaccharides of several serotypes of S. pneumoniae have been conjugated with carrier proteins, used by Hib, (86,87) and to a new outer membrane protein of non-typeable Haemophilus. (88)

At present, a varied quantity of serotypes has been used to develop these vaccines. A vaccine with seven serotypes (4, 6B, 9V, 14, 18C, 19F, 23F) has been commercially released. This vaccine contains 2 of polysaccharides of six serotypes and 4 of serotype 6B, conjugated with CRM197. This vaccine has proved safe and immunogenic in several studies, especially when used in four doses, 2-4-6 months of life and booster doses between 12 and 15 months of life. Six out of these seven serotypes require only two doses of the vaccine to produce a good antibody response; only serotype 6B requires three doses to produce a significant response. Two important studies were carried out in 1995 to assess the efficiency of this vaccine. One study, conducted in Finland, included 2,497 children, selected after their second month of life, and randomized to receive four doses of Pnc CRM or PncOMP, and a control group that received the hepatitis B vaccine. The established outcomes aimed at determining the efficacy of the vaccine in the prevention of acute otitis media and the status of patients with S. pneumoniae in their pharynx. The results of the study revealed a 7% reduction in the total episodes of acute otitis media and an 8.9% reduction in medical appointments, in both vaccinated children and in partially covered children. Higher efficiency (22.8%) was observed when assessing the reduction in the placement of tympanic membrane ventilation tubes.

The other study was carried out in California, in a population of 38,000 children, randomized at a 1:1 ratio, by applying four doses of vaccines (2-4-6 months of life and booster between 12 and 15 months of life): Pnc CRM (7 serotypes) versus meningococcal conjugate vaccine (control group). The occurrence of invasive diseases, evaluated 14 days after the first three doses, was very high(89-91) (Table 2).

Table 2 -
Efficacy regarding the invasive disease caused by serum types contained in the vaccine

The impact of vaccination on the reduction of respiratory disease (pneumonia) was also evaluated (Table 3).

Table 3 -
Efficacy of the vaccine against pneumonia

Other studies have confirmed the efficiency of the vaccine, but in a recent communication, and as a greater number of patients were added, the vaccine has shown to be effective, with a 22.2% reduction of pneumonias of any etiology. (92)

The heptavalent vaccine has covered most serotypes responsible for invasive disease in countries in the northern hemisphere. However, this does not occur in the southern hemisphere, where other serotypes are involved, especially serotypes 1 and 5, with a prevalence between 20 and 40%. (93,94) Therefore, new vaccines with a great number of serotypes are still under development (9 and 11 serotypes). In the latter case, a vaccine that uses Protein D (an outer membrane protein of Haemophilus) as carrier protein, has been under development. (88)

Another objective is the possibility of altering the serotypes that cause the invasive disease. Even if the objective is not achieved, alterations are observed in the serotypes involved in the carrier statuses. The capsular polysaccharides are specific to each serotype and, although there is cross-immunogenicity between some of them, conjugate vaccines have technical limitations as to the inclusion of more serotypes. Currently, antipneumococcal vaccines have been developed with other components of bacterial structure, common to the more than 80 types of serotypes available.

Different proteins of the bacterial wall have been studied, such as PsaP and PsaA. In preclinical studies, both proteins have proved safe and immunogenic. Other components of the S. pneumoniae, structure, such as pneumolysin, have been studied as well (94).

The current vaccines, especially the pneumococcal conjugate ones, have shown high efficiency in the prevention of invasive disease, but have had a smaller impact on the occurrence of pneumonias and otitis media. However, due to the high prevalence of these infections, such impact is very significant. Several studies are still necessary to determine the impact of conjugate vaccines on the carrier status and their implications.

The development of new vaccines should continue, regardless of whether they incorporate a greater number of serotypes or whether they use bacterial cell components. It is also necessary to cut down costs so that their use can be extended to the populations of developing countries, in which the incidence rates of these diseases are higher.