Vaccines

Essential facts about the pneumococcus

1. Disease caused by the pneumococcus is a growing and increasingly urgent global problem.

2. Pneumococcal disease is the leading cause of child pneumonia deaths, as well as the

leading cause of childhood meningitis deaths, outside of meningococcal epidemics.

3. The pneumococcus kills more than 1.6 million people including 900000 children under five each

year.

4. HIV infected children are 20 to 40 times more likely to get pneumococcal disease.

5. Pneumonia is the leading infectious cause of child mortality worldwide, causing an estimated

1.9 million (or 19%) of the estimated 10 million child deaths each year.

6. Pneumococcal disease is VACCINE PREVENTABLE, and every child has a right to pneumococcal vaccination

7. Pneumococcal conjugate vaccine has been proven to be safe and effective in children in

both low and middle-income countries and high-income countries. Two trials in Africa (one in

The Gambia and the other in South Africa) found the pneumococcal vaccine to have an efficacy

of 77-83% in HIV non-infected children against vaccine sero-types.

8. Pneumococcal vaccine is safe and effective in HIV infected children resulting in a 65% reduction

in vaccine-serotype invasive disease.

9. Early identification of severe pneumonia and treatment with oxygen and appropriate antibiotics

may reduce deaths.

10. Avoidance of crowding and smoke from indoor air pollution could help in reducing spread and prevalence of pneumonia

Figure 1: Global burden of pneumonia

Source: GAVI Alliance

What is pneumococcal disease?

Streptococcus pneumoniae (S. pneumoniae also known as the pneumococcus) causes a wide range of important diseases, from common upper respiratory tract infections (such as sinusitis and otitis media) to severe invasive disease such as pneumonia, meningitis and septicaemia. Pneumococcus occasionally causes other infections such pericarditis, osteomyelitis, arthritis, and soft tissue infections

Pneumococcal disease causes approximately 900 000 deaths in children less than five years of age around the world each year, mostly in children under two in low-income and middle-income countries. In high-income countries, elderly persons also carry a large disease burden. Conditions associated with increased risk of serious pneumococcal disease include HIV infection, sickle-cell anaemia and a variety of chronic diseases.

The pathogen

Pneumococci are Gram-positive encapsulated, lancet-shaped cocci, which usually occur in pairs (diplococci). The polysaccharide capsule is an essential virulence factor for invasive pneumococcal disease. Based on the differences in the composition of this capsule, there are about 91 distinct pneumococcal serotypes. Further differentiation into clones may be achieved using molecular technologies. The spectrum of prevailing capsular types varies with age, time and geographical region, although common serotypes are consistently identified throughout the world. Globally, about 20 serotypes are associated with >80% of invasive pneumococcal disease occurring in all age groups; the 13 most common serotypes cause at least 75% of invasive disease in children.

How is pneumococcal infection spread?

The pneumococcus resides in the naso-/ oro-pharynx and is spread by coughing, sneezing, or contact with respiratory secretions. There is a high prevalence of nasopharyngeal clonisation (40-80% in low- and middle-income countries) in children, as well as in ceratin adults, especially in industrialising countries. Transient nasopharyngeal colonisation – not disease – is the usual outcome of exposure to pneumococci. Disease is caused either by contiguous spread to the sinuses or the middle ear, aspiration into the lower respiratory tract causing pneumonia, or by invasion of the bloodstream with or without seeding of secondary sites. Why it suddenly invades the body and causes disease is unknown.

Clinical picture of pneumococcal infection

Invasive pneumococcal disease refers to the presence of pneumococcus in a normally sterile site such as blood or cerebrospinal fluid. Invasive pneumococcal disease can take one of three forms: a mild, usually transient, occult bacteraemia without a focus of infection; severe disease with a focus of infection such as pneumonia or meningitis; or full-blown clinical sepsis with cardiovascular compromise.

Pneumonia

Pneumonia is a severe acute respiratory infection in the lungs, which become filled with pus and fluid, making the absorption of oxygen difficult. Symptoms include high fever, chills, shortness of breath, productive cough, and chest pain. Pneumonia is the most common serious disease manifestation of pneumococcal disease. Pneumococcal pneumonia is more frequent than can be confirmed by positive blood cultures, and up to half of pneumonia deaths in children is attributed to pneumococcus.

Meningitis

Meningitis is an inflammation of the lining surrounding the brain and spinal cord. High fever, headache and a stiff neck are common symptoms of meningitis, as are nausea, vomiting, an aversion to bright lights, sleepiness, confusion, and seizures. Meningitis is the most serious clinical manifestation of invasive pneumococcal disease. It is more common in young children: the proportion of invasive pneumococcal disease cases involving meningitis is about 2-fold higher among young children in Africa and Asia compared to older children and adults.

Sepsis

Sepsis can progress rapidly to septic shock and multi-organ failure due to a lack of oxygen reaching important organs in the body. Symptoms include fever or abnormally low body temperature, chills, fast heart rate, low blood pressure, lethargy, confusion, or irritability, skin rash, inability to eat or drink, and/or decreased urine output.

Otitis media and sinusitis

These conditions represent non-invasive pneumococcal disease resulting from contiguous spread from nasopharyngeal mucosa. Up to half of all cases of otitis media are attributed to pneumococcus. Acute otitis media is more common with newly acquired nasopharyngeal colonising strains versus strains associated with long-term colonisation.

Risk factors

Persons with a high risk of serious pneumococcal disease include children less than 2 years of age, persons over 65 years old, HIV infected persons, malnourished people and those with sickle cell disease. Other persons at presumed high risk include those with chronic lung, heart or renal disease, diabetes, and malignanacies.

The incidence of pneumococcal disease

Pneumococcal diseases are a major public health problem all over the world with about 1.6 million cases of fatal pneumococcal disease occurring worldwide annually, mostly in infants and the elderly, according to WHO. In addition, immunocompromised individuals of all ages are at increased risk. Nine in ten child deaths from serious pneumococcal diseases occur in low-income and middle-income countries. Ten countries in sub-Saharan Africa and Asia account for more than 60% of pneumococcal diseases worldwide. Among Indian children, pneumonia causes a quarter of all deaths.

Management of pneumonia

Integrated Management of Childhood Illness

WHO and UNICEF recommend the use of the guidelines for Integrated Management of Childhood Illness (IMCI) to manage children with pneumonia and suspected bacterial infection. IMCI aims to reduce death, illness and disability, and to promote improved growth and development among children under five years of age.

This integrated case management approach relies on case detection using simple clinical signs and empirical treatment. As few clinical signs as possible are used. The signs are based on expert clinical opinion and research results, and strike a careful balance between sensitivity and specificity. The treatments are developed according to action-oriented classifications rather than exact diagnosis. The IMCI process can be used by doctors, nurses and other health professionals who see sick infants and children aged from 1 week up to five years. It is a case management process for a first-level facility such as a clinic, a health centre or an outpatient department of a hospital. The tables below summarise the IMCI approach for classifying diseases that manifest by cough or breathing difficulty (Table 1), ear problem (Table 2), and a possible bacterial infection (Table 3).

In health facilities, the IMCI case management strategy promotes the accurate identification of childhood illnesses in outpatient settings, ensures appropriate combined treatment of all major illnesses, strengthens the counselling of caretakers, and speeds up the referral of severely ill children (such as those with invasive pneumococcal disease). In the home setting, it promotes appropriate care-seeking behaviours, improved nutrition and preventive care, and the correct implementation of prescribed care.

Table 1: IMCI classification table for cough or difficult breathing

SIGNS

CLASSIFY AS

IDENTIFY TREATMENT

(Urgent pre-referral treatments are in bold print.)

· Any general danger sign or

· Chest wall indrawing or

· Stridor in calm child

Severe pneumonia

· Give first dose of an appropriate antibiotic

· Refer URGENTLY to hospital.

Fast breathing

Non-severe pneumonia

· Give an appropriate oral antibiotic for 5 days

· Soothe the throat and relieve the cough with a safe remedy

· Advise mother when to return immediately

· Follow-up in 2 days

No signs of pneumonia

No pneumonia: cough or cold

· If coughing more than 30 days, refer for assessment

· Soothe the throat and relieve the cough with a safe remedy

· Advise mother when to return immediately

· Follow-up in 5 days if not improving.

General danger signs:

· The child is not able to drink or breastfeed

· The child vomits everything

· The child had convulsions

· The child is lethargic or unconscious.

Criteria for fast breathing

· 2 months to 12 months old: 50 breaths or more per minute

· 12 months to 5 years old: 40 breaths or more per minute

Table 2: IMCI classification table for ear problem

SIGNS	CLASSIFY AS	IDENTIFY TREATMENT (Urgent pre-referral treatments are in bold print.)
Tender swelling behind	Mastoiditis	· Give first dose of an appropriate antibiotic. · Give first dose of paracetamol for pain. · Refer URGENTLY to hospital.
· Pus is seen draining from the ear and discharge is reported for less than 14 days, or · Ear pain	Acute ear infection	· Give an oral antibiotic for 5 days · Give paracetamol for pain · Dry the ear by wicking · Follow-up in 5 days
Pus is seen draining from the ear and discharge is reported for 14 days or more	Chronic ear infection	· Dry the ear by wicking · Follow-up in 5 days
No ear pain and No pus seen draining from the ear	No ear infection	No additional treatment

Table 3: IMCI classification for possible bacterial infection

SIGNS

CLASSIFY AS

IDENTIFY TREATMENT

(Urgent pre-referral treatments are in bold print.)

· Convulsions, or

· Fast breathing, or

· Severe chest indrawing or

· Nasal flaring, or

· Grunting, or

· Bulging fontanelle, or

· Pus draining from ear, or

· Umbilical redness extending to the skin, or

· Fever (37.5 °C* or above or feels hot) or low body temperature (less than 35.5 °C* or feels cold), or

· Many or severe skin pustules, or

· Lethargic or unconscious or

· Less than normal movement

Possible serious bacterial infection

· Give first dose of intramuscular antibiotics

· Treat to prevent low blood sugar

· Advise mother how to keep the infant warm on the way to hospital

· Refer URGENTLY to hospital

Red umbilicus or draining pus, or

Skin pustules

Local bacterial infection

· Give an appropriate oral antibiotic for 5 days

· Teach the mother to treat local infections at home

· Advise mother to give home care for the young infant

· Follow-up in 2 days

* These thresholds are based on axillary temperature. The thresholds for rectal temperature readings are approximately 0.5 °C higher.

Treatment

Antibiotics constitute the backbone of treatment for pneumococcal disease, with the choice of antibiotic dependent the clinical syndrome (i.e. pneumonia, meningitis, sepsis or otitis media), the age of the patient, and local antibiotic resistance patterns. Treatment regimens need to be chosen based on their efficacy in local settings as some areas may have high levels of resistance to certain antibiotics, rendering those drugs less effective for treating pneumonia.

Antibiotic-resistant pneumococcal infections are a growing public health problem worldwide. There is regional variation in the rates of penicillin-resistant pneumococcus, due in part to local prescribing practices of antibiotics, laboratory practices that affect the accuracy of testing for antibiotic resistance and the actual patient population tested. For example, hospital patients are generally sicker and may have been exposed to more antibiotics in the past, and so the prevalence of penicillin resistance may be higher in this population compared to a population selected at random from the community.

In general, pneumococcal pneumonia can be successfully treated with amoxicillin, even in places with reduced susceptibility to amoxicillin because of the favourable pharmacokinetic / pharmacodynamic profile of amoxicillin.

Prevention

Given the challenges to obtaining appropriate care for children with pneumococcal disease, the risk of inappropriate therapy contributing to antibiotic resistance and the cost of illness, prevention is the best option for controlling pneumococcal disease. Prevention strategies for pneumococcal disease include adequate nutrition, and immunisation.

Zinc is a micronutrient that plays a key role in a wide range of enzymatic processes in human growth, metabolism and immune function. Limited evidence show that in low-income countries, zinc supplementation of children under five results in 41% reduction in the incidence of pneumonia.

Pneumococcal vaccines

There are many serotypes of Streptococcus pneumoniae and two types of vaccine currently available. A 23-valent polysacharide vaccine is indicated for high-risk groups of adult and older children, where as a 7-valent (soon to be 10-valent and 13-valent) polysacharide-protein conjugate vaccine is used in children under 9 years of age.

The 23-valent unconjugated polysaccharide vaccine

The 23-valent vaccine contains a purified capsular polysaccharide antigen from 23 serotypes of pneumococcus that cause 88% of invasive pneumococcal disease, is approved for use in adults and children older than two years of age.

The vaccine is recommended for adults 65 years or older and persons two years and older with chronic illness, anatomic or functional asplenia, HIV infection (especially if HIV viral load < 100 000 copies/ml) or other immunosuppressive conditions. This vaccine is not recommended for routine use in children.

The 7-valent conjugate vaccine

The 7-valent conjugate vaccine (PCV-7) consists of pneumococcal polysaccharide conjugated to a diphtheria protein (CRM₁₉₇) and seven serotypes of the pneumococcus (4, 6B, 9V,14, 18C, 19F, and 23F). These serotypes cause 86% of bacteraemia and 83% of meningitis among children younger than 6 years of age in the United States.

The results of the first PCV-7 trial, reported in 2000, showed a protective efficacy of 93.9% against invasive pneumococcal disease caused by vaccine serotypes among children who received at least one dose of the vaccine. Following the trial (which was conducted in the United States), PCV-7 was introduced into the United States national immunisation programme in 2000. Five years after the introduction, disease surveillance results showed a 77% decrease in invasive pneumococcal disease among children aged 5 years and younger. The incidence among people aged above 5 years who did not receive the vaccine, also reduced substantially, probably as a result of decreased transmission from younger vaccinated children (i.e. "indirect protection").

In low and middle-income countries, pneomococcal vaccine trials have been conducted in The Gambia and South Africa. A randomised controlled trial in the Gambia found that the efficacy of 3 doses of PCV-9 against vaccine-type invasive pneumococcal disease was 77%. A similar study in South Africa found 83% protective efficacy against vaccine-type invasive pneumococcal disease in HIV-negative children and 65% efficacy in HIV-positive children.

PCV-7 is well tolerated and has a good safety profile. It induces a T-cell dependent immune response characterised by immune memory as well as a booster antibody response on subsequent challenge with the pneumococcal polysaccharides included in the vaccine. It also stimulates mucosal immunity, resulting in reduced nasopharyngeal carriage. The indrect protection effect observed with this vaccine is most likely the result of reduced transmission of vaccine-type pneumococci in the community as a result of decreased carriage in young children and reduced transmission in the community. PCV-7 is highly immunogenic in all age groups, but it is currently licensed for use only in children aged less than 9 years. In young children, protection against invasive pneumococcal disease caused by vaccine serotypes may exceed 90%; however, corresponding protection against acute otitis media due to vaccine-serotype is 55%.

WHO’s strategy on pneumococcal vaccines

The World Health Organization (WHO) recommends that countries should prioritise introducing the 7-valent vaccine, when mortality among children under five is more than 50 per 1000 live births or more than 50,000 children die annually. The recommendation continues that countries with a high prevalence of HIV or other conditions which increase the risk of pneumococcal disease, should vaccinate with the 7-valent vaccine. The vaccine may be administered concomitantly with other vaccines in the Expanded Programme on Immunisation provided that separate syringes and sites of injection are used. The most effective vaccination strategy is a three-dose schedule for infants given at the same time as the diphtheria–tetanus–pertussis (DPT) vaccine. The introduction of pneumococcal vaccine into the EPI should be accompanied by appropriate surveillance for invasive pneumococcal disease to establish a baseline measure and to monitor the impact of vaccination, including the occurrence and magnitude of replacement disease.

In low-income countries, pneumococcal diseases are often caused by additional serotypes of Streptococcus pneumoniae. As a result, 10-valent and 13-valent vaccines (which include additional serotypes and provide broader coverage) are needed and are currently being licensed. WHO recommends that such countries should consider switching from the 7-valent vaccine to these broader serotype conjugated vaccines as they become available. The 10-valent vaccine uses protein D from H. influenzae as the protein carrier and contains the serotypes in PCV-7 plus serotypes 1, 5, and 7F. The 13-valent vaccine has the same carrier protein as PCV-7 and contains serotypes of the 10-valent vaccine plus 3, 6A and 19A.

African conjugate pneumococcal vaccine trials

South African researchers found that a nine-valent conjugate vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83% and in HIV-infected children, the efficacy was 65 percent. The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection.

Researchers in the Gambia found that a nine-valent conjugate was 77 percent effective in preventing pneumococcal infections caused by the vaccine serotypes. As a result, there were 37 percent fewer cases of pneumonia in the children who received the vaccine compared with children who received the control vaccine. Overall, the vaccine reduced childhood mortality by 16 percent in children who received it. In addition, the vaccine significantly reduced the need for hospitalization. Vaccinated children had 15 percent fewer hospital admissions than those who did not.

The Soweto, South African trial

Reference: Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N,Pierce N, et al. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Eng J Med 2003;349:1341-48.

Institution: Medical Research Council, University of the Witwatersrand, National Institute for Communicable Diseases, Respiratory and Meningeal Pathogens Research Unit, Johannesburg, South Africa.

Background: Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children. We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a randomized, double-blind study in Soweto, South Africa.

Methods: At 6, 10, and 14 weeks of age, 19,922 children received the 9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin (CRM197), and 19,914 received placebo. All children received Haemophilus influenzae type b conjugate vaccine. Efficacy and safety were analyzed according to the intention-to-treat principle.

Results: Among children without human immunodeficiency virus (HIV) infection, the vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83 percent (95 percent confidence interval, 39 to 97; 17 cases among controls and 3 among vaccine recipients). Among HIV-infected children, the efficacy was 65 percent (95 percent confidence interval, 24 to 86; 26 and 9 cases, respectively). Among children without HIV infection, the vaccine reduced the incidence of first episodes of radiologically confirmed alveolar consolidation by 20 percent (95 percent confidence interval, 2 to 35; 212 cases in the control group and 169 in the vaccinated group) in the intention-to-treat analysis and by 25 percent (95 percent confidence interval, 4 to 41; 158 and 119 cases, respectively) in the per-protocol analysis (i.e., among fully vaccinated children). The incidence of invasive pneumococcal disease caused by penicillin-resistant strains was reduced by 67 percent (95 percent confidence interval, 19 to 88; 21 cases in the control group and 7 in the vaccinated group), and that caused by strains resistant to trimethoprim-sulfamethoxazole was reduced by 56 percent (95 percent confidence interval, 16 to 78; 32 and 14 cases, respectively).

Conclusions: Vaccination with a 9-valent pneumococcal conjugate vaccine reduced the incidence of radiologically confirmed pneumonia. The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection.

The Gambia trial

Reference: Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, et al. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet 2005;365:1139-46.

Institution: Medical Research Council Laboratories, Banjul, The Gambia.

Methods: We undertook a randomised, placebo-controlled, double-blind trial in eastern Gambia. Children age 6-51 weeks were randomly allocated three doses of either pneumococcal conjugate vaccine (n=8718) or placebo (8719), with intervals of at least 25 days between doses. Our primary outcome was first episode of radiological pneumonia. Secondary endpoints were clinical or severe clinical pneumonia, invasive pneumococcal disease, and all-cause admissions. Analyses were per protocol and intention to treat.

Findings: 529 children assigned vaccine and 568 allocated placebo were not included in the per-protocol analysis. Results of per-protocol and intention-to-treat analyses were similar. By per-protocol analysis, 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo. Pneumococcal vaccine efficacy was 37% (95% CI 27-45) against first episode of radiological pneumonia. First episodes of clinical pneumonia were reduced overall by 7% (95% CI 1-12). Efficacy of the conjugate vaccine was 77% (51-90) against invasive pneumococcal disease caused by vaccine serotypes, 50% (21-69) against disease caused by all serotypes, and 15% (7-21) against all-cause admissions. We also found an efficacy of 16% (3-28) against mortality. 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo.

Interpretation: In this rural African setting, pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease, and can substantially reduce admissions and improve child survival. Pneumococcal conjugate vaccines should be made available to African infants.

GAVI support for pneumococcal vaccine in Africa

GAVI support for this vaccine became available to countries for the first time in 2007 and as at January 2009, 11 countries - including 7 African countries - were approved for this type of support. Roll-out in these countries is expected to start from 2009 onward.

Of the 72 GAVI currently eligible countries, 71 countries currently qualify for support for pneumococcal vaccine, because their immunisation coverage for the third dose for diphtheria, pertussis and tetanus (DTP3) has reached at least 50% and their government is not already funding the vaccine.

References and other resources

General

Pneumococcal Vaccine Accelerated Development and Introduction Plan (PneumoADIP)

Advance Market Commitments (AMCs) to stimulate the development of vaccines for low-income countries

Integrated Management of Childhood Illness (IMCI)

Pneumococcal Awareness Council of Experts (PACE)

Pneumococcal vaccines

WHO postion paper on the pneumococcal conjugate vaccine for childhood immunisation (Wkly Epidemiol Rec 2007 Mar;82:93-104)

Report on the safety of the pneumococcal conjugate vaccine by the Global Advisory Commitee on Vaccine Safety (Wkly Epidemiol Rec 2007 Jan;82:17-24)

WHO Position Paper on the 23-valent pneumococcal polysaccharide vaccine (Wkly Epidemiol Rec 2008 Oct;83:373-84)

Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N, et al. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003;349:1341-48.

Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS Okoko JB, et al. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet 2005;365:1139-46.