Bacille Calmette-Guérin Vaccine

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis and is spread from person to person through the air; it primarily causes disease in the lung, although it can spread to many parts of the body. Infection with M. tuberculosis may lie dormant for years. In 2012, the WHO estimated a global burden of 8.6 million cases and 1.3 million deaths due to tuberculosis; 55,000 of these were in children under age five years, 95 percent of which occurred in LMICs. Co-infection with human immunodeficiency virus (HIV) greatly increases the risk of developing active tuberculosis. The treatment of tuberculosis worldwide is becoming more complicated because of the rise of multidrug-resistant strains (Bloom and others, forthcoming; Connelly Smith, Orme, and Starke 2013; WHO 2015a).

BCG vaccine is a live-attenuated strain of a related mycobacterium, Mycobacterium bovis, originally isolated from an infected cow and attenuated through repeated passage. BCG is most effective against tuberculous meningitis and disseminated (miliary) tuberculosis. However, BCG vaccination does not prevent M. tuberculosis infection in childhood, when most infections occur, or reactivation of latent infection and pulmonary tuberculosis later in life, which is the principal source of community transmission (WHO 2004). In 2012, BCG was included in routine infant immunization schedules in 159 of 194 WHO member states; worldwide coverage was estimated to be 90 percent in 2012 (WHO, UNICEF, and World Bank 2002). Approximately 100 million infants receive BCG annually; more than 4 billion people have been vaccinated (Connelly Smith, Orme, and Starke 2013). The 100 million BCG vaccinations given worldwide to infants in 2002 prevented approximately 30,000 cases of tuberculous meningitis and 11,000 cases of miliary tuberculosis (Trunz, Fine, and Dye 2006).

Vaccination is recommended for all infants in countries with high tuberculosis disease burden and infants at high risk of exposure in low-burden countries. Because it is a live-attenuated vaccine, BCG is not recommended for immunocompromised children, including those with congenital severe combined immunodeficiency syndrome and those with symptomatic HIV infection.

Tuberculosis will not be eliminated without new, more effective tuberculosis vaccines (Connelly Smith, Orme, and Starke 2013). For the prevention of severe childhood diseases, a single BCG dose is recommended as soon as possible after birth (WHO 2004). BCG is the only vaccine in the EPI program routinely administered by intradermal injection, which requires specific injection supplies and health care worker training. BCG is produced by a large number of countries using different vaccine seed strains, which may contribute to the variability in effectiveness observed in different studies.

Diphtheria, Tetanus, and Pertussis Vaccine

Despite progress, these three bacterial diseases of infancy and early childhood remain endemic in some countries. Diphtheria is a respiratory illness characterized by membranous inflammation of the upper respiratory tract caused by toxin-producing Corynebacterium diphtheriae and is transmitted through respiratory droplets and coughing. Before vaccination, an estimated 1 million cases and 50,000–60,000 deaths occurred annually (Walsh and Warren 1979). In 2008, only 7,000 cases of diphtheria were reported; more than 85 percent of these occurred in India (WHO and UNICEF 2014). Tetanus is caused by a toxin produced by Clostridium tetani, a ubiquitous organism found in the soil and transmitted through contamination of wounds or unsterile procedures, including care of the umbilical cord. Neonatal tetanus is mostly present in LMICs, resulting in an estimated 34,481 deaths in 2015 in children in LMICs, which account for 99 percent of all under-five tetanus deaths worldwide (Liu and others 2016). Pertussis, or whooping cough, is a highly communicable respiratory illness caused by Bordetella pertussis and characterized by paroxysmal cough that may last for many weeks. Estimates from the WHO suggest that about 63,000 children died from this disease in 2008, 95 percent of them in LMICs (Black and others 2010).

DTP vaccines are composed of inactivated diphtheria and tetanus toxins (referred to as toxoids) and pertussis antigens, either killed, whole-cell Bordetella pertussis or purified antigens (acellular pertussis [aP] vaccine). Whole-cell pertussis acts as a potent adjuvant that improves the immune response to diphtheria and tetanus toxoids, but periodic boosting is required because of waning immune responses; waning may occur more quickly with aP vaccines (Edwards and Decker 2013). DTP vaccines combined with hepatitis B and Haemophilus influenzae type b (Hib) antigens are widely used in LMICs, while combination vaccines with aP are common in upper-middle- and high-income countries. Because the risk of pertussis complications is highest in infants too young to be vaccinated, maternal vaccination is a strategy that could protect young infants (CDC 2011).

DTP vaccine coverage is an important indicator of immunization program performance. Initiatives to strengthen routine immunization services often monitor progress as measured by coverage with the third DTP dose (DTP3) in infancy, which requires multiple immunization visits in the first year of life. The difference between coverage with the first versus the third DTP dose, often called dropout, measures loss to follow-up and challenges to completion of infant vaccinations. Many newer vaccines, including pneumococcal, meningococcal, and rotavirus vaccines, have adapted to DTP immunization schedules to reach the maximum number of children during scheduled immunization visits.

DTP vaccines are included in routine childhood immunization programs in all 194 WHO member states. Global DTP3 coverage rose from 20 percent in 1980 to 84 percent in 2013 (WHO and UNICEF 2014), preventing 76,000 deaths from diphtheria and 1.6 million deaths from pertussis annually. In conjunction with improved maternal immunization against tetanus, the vaccines prevented approximately 408,000 deaths from tetanus (WHO 2013a). Despite increased coverage, more than 20 million infants remained unvaccinated in 2013 (WHO and UNICEF 2014). More than 80 percent of these children live in Gavi-eligible countries. If these countries achieved and maintained their DTP3 coverage at 90 percent between 2015 and 2020, 439,000 deaths and 16 million cases of pertussis could be averted during the 10 years from the scale-up (Stack and others 2011).

Polio Vaccine

The goal of universal polio vaccination is eradication. In 1988, when the Global Polio Eradication Initiative was established, poliomyelitis crippled more than 350,000 children each year, with transmission of wild poliovirus serotypes (1, 2, and 3) reported from 125 countries (WHO 2014c). From January to December 2015, only 66 cases of wild poliovirus type 1 were reported worldwide, compared with 359 cases in January to December 2014, and no cases of wild poliovirus had been reported on the African continent for 12 months; wild type 2 polioviruses have not been identified since 1999; and the last case of wild type 3 poliovirus occurred in 2012 (Global Polio Eradication Initiative 2013; WHO 2014b).

Implementation of routine childhood immunization and supplemental immunization activities with oral polio vaccine (OPV) containing attenuated polioviruses of all three types substantially decreased cases in LMICs and eliminated poliovirus circulation in the WHO regions of the Americas, Europe, Western Pacific, and South-East Asia. Clinical trials showed that three doses of OPV were needed for greater than 90 percent protection against paralytic poliomyelitis. However, the immune response was lower among children in LMICs, requiring more vaccine doses to achieve the high levels of population immunity necessary for elimination (Estívariz and others 2012; Grassly and others 2007). In 2014, the WHO recommended that all countries using OPV include at least one dose of inactivated polio vaccine (IPV) in their routine immunization schedule (WHO 2014c). Most immunization schedules in LMICs include a three-dose primary polio immunization schedule, and many include booster doses in the second year of life. For high-risk countries, the WHO recommends four doses beginning as soon as possible after birth, with at least one dose of IPV at age 14 weeks if only one IPV dose is given.

There are several steps to the Polio Eradication and Endgame Strategic Plan 2013–2018, and this transition in polio vaccination strategy has several phases. First, all OPV-using countries should introduce at least one dose of IPV (containing inactivated polioviruses of all three types) to boost immunity to poliovirus type 2 (WHO 2014b). Then, trivalent OPV will be replaced with more immunogenic bivalent OPV containing type 1 and 3 viruses. IPV introduction will pave the way for future total cessation of all OPV use after eradication has been achieved. Most high-income countries adopted routine childhood immunization with IPV to prevent rare cases of paralytic polio caused by OPV. However, achieving high coverage with IPV will require strengthening of routine immunization services.

Measles Vaccine

Measles is one of the most contagious diseases of humans (Fine and Mulholland 2013). It is caused by a paramyxo-virus, manifesting as a febrile rash illness, which can result in multiple life-threatening complications, including pneumonia, diarrhea, and encephalitis. In 2000, measles was the leading vaccine-preventable cause of childhood deaths and the fifth leading cause of under-five mortality; that year, measles alone accounted for 5 percent of the estimated 10.9 million deaths among children under age five years (Strebel and others 2012). By 2010, measles-related deaths had declined by 75 percent following accelerated measles control activities in Sub-Saharan Africa and other regions (Simons and others 2012); declines in measles-related deaths accounted for almost 10.1 percent of overall declines in childhood mortality from 2000 to 2015 (Liu and others 2016). Further progress is expected as countries implement measles elimination strategies; as of 2014, all six WHO regions had established target dates for measles elimination.

Measles vaccination can prevent illness and death directly among vaccinated persons and indirectly among unvaccinated persons as a result of decreased transmission. In countries with ongoing transmission of measles and high risk of measles among infants, the WHO recommends vaccination at age nine months when protection provided by maternal antibody wanes and seroconversion rates improve among infants. In countries with low rates of measles transmission, the WHO recommends the first dose of vaccine at age 12 months to take advantage of higher seroconversion rates achieved at this age (Strebel and others 2012).

Between 1980 and 2011, global measles vaccination coverage rose from 18 percent to 84 percent globally (WHO 2013d; WHO, UNICEF, and World Bank 2002). In one analysis, a projected 624 million children in Gavi-eligible countries would be vaccinated with one dose of measles-containing vaccine between 2011 and 2020, averting 10.3 million deaths relative to a hypothetical scenario in which countries were not administering measles vaccine (Lee and others 2013).

Because of its high risk of contagion, high levels of immunity are needed to interrupt measles transmission. A two-dose strategy is deemed essential for measles elimination, to immunize children who missed the first dose and protect up to 15 percent of children who do not seroconvert after primary immunization (WHO 2013d). Childhood immunization schedules in many countries include two doses. In countries with poor access to preventive services, the second opportunity for measles vaccination is most often provided through nationwide supplementary immunization activities or mass campaigns.

Hepatitis B Vaccine

Hepatitis B vaccine is included in routine infant immunization schedules to prevent serious disease and death later in life caused by chronic infection with hepatitis B virus, a member of the hepadnavirus family. Hepatitis B virus is a blood-borne pathogen that may also be transmitted sexually. Hepatitis B, one of five viruses known to cause hepatitis in humans, is responsible for most of the worldwide hepatitis burden: more than 2 billion people have been infected with hepatitis B virus, and 360 million have become chronically infected (WHO 2010b). Chronic hepatitis B virus infection is the leading cause of cirrhosis and cancer of the liver, which result in approximately 600,000 deaths annually (Goldstein and others 2005). Hepatitis B virus transmission may occur prenatally and during early childhood, adolescence, and adulthood. Vaccination is more than 95 percent effective in infants and more than 72 percent effective in preventing perinatal transmission. Vaccination must be part of a comprehensive prevention strategy. Humans are the only reservoir of hepatitis B virus, making disease elimination possible (WHO 2010b).

Modern hepatitis B vaccines containing recombinant hepatitis B virus surface antigen (HBsAg) were introduced in 1986 (Van Damme and others 2013). The WHO has recommended routine infant vaccination against hepatitis B since 1992. In 2013, hepatitis B vaccine was included in routine infant immunization schedules in 94 percent of 194 WHO member states. Infant immunization schedules include at least three doses of hepatitis B vaccine, which may be combined with other antigens, such as DTP and Haemophilus influenzae type b. In 2013, worldwide coverage with three doses of hepatitis B vaccine was estimated to be 81 percent. In countries with a high prevalence of hepatitis B virus infection, the WHO recommends administering the first dose within 24 hours of birth to prevent perinatal transmission. In 2013, 93 countries included hepatitis B birth dose in their routine immunization schedules, with global coverage estimated to be 38 percent. Better birth dose coverage and monitoring are needed; timely delivery of birth dose should be a performance measure of immunization programs (WHO 2013h).

Haemophilus influenzae Type b Vaccine

Haemophilus influenzae is a Gram-negative bacterium surrounded by a polysaccharide capsule, which is a major virulence factor. While six serotypes (a, b, c, d, e, f) and unencapsulated strains cause disease—including meningitis, pneumonia, septicemia, epiglottitis, cellulitis, septic arthritis, osteomyelitis, and otitis media (mainly due to unencapsulated H. influenzae)—Hib was the leading cause of meningitis in children under age five years in most countries before widespread vaccination (Bennett and others 2002). The mean case fatality rate (CFR) of Hib meningitis was 67 percent (44 percent to 75 percent) in Sub-Saharan Africa and 43 percent (23 percent to 55 percent) globally. In 2000, before widespread Hib vaccination, Hib caused an estimated 371,000 deaths (Watt and others 2009). By 2008, Hib vaccines were used in 136 countries, and estimated deaths had fallen to 203,000 (Black and others 2010; WHO 2013b).

Evidence from several clinical trials of Hib conjugate vaccine demonstrated the importance of Hib in causing severe pneumonia; Hib accounted for 25 percent of severe pneumonia in The Gambia and 22 percent in Chile (Levine and others 1999; Mulholland and others 1997). Hib pneumonia rates are higher than Hib meningitis rates; consequently, pneumonia accounted for the majority (79 percent) of the approximately 200,000 Hib-related deaths worldwide in children ages 1–59 months in 2010 (WHO 2013h).

The multiple formulations of Hib conjugate vaccines include several different conjugated proteins and combination vaccines, such as the most widely used pentavalent vaccine (DTP–Hepatitis B–Hib). Hib conjugate vaccines are more than 80 percent effective against Hib meningitis, sepsis, and bacteremic pneumonia; in most Sub-Saharan African countries that have introduced Hib vaccine into the national program, Hib disease has virtually disappeared (Adegbola and others 2005; Cowgill and others 2006; WHO 2006b). However, Hib vaccines likely have reduced efficacy in HIV-infected children, and evidence from South Africa suggests a booster dose might be required (Mangtani and others 2010). In many settings, three doses of Hib vaccine in infancy may control the disease and do not appear to increase rates of H. influenzae disease caused by serotypes other than type b (Ribeiro and others 2007; Zanella and others 2011). By 2013, 186 countries had introduced Hib vaccines, and as of 2014, all 73 Gavi countries vaccinated against Hib alongside hepatitis B, diphtheria, tetanus, and pertussis through the pentavalent vaccine as part of their routine infant immunization programs.

Future needs include introduction of Hib vaccine into countries that have not yet introduced it, particularly in Asia.

Pneumococcal Conjugate Vaccine

Streptococcus pneumoniae, the pneumococcus, is a Gram-positive encapsulated bacterium commonly found in the respiratory tract. Pneumococci are surrounded by polysaccharide capsules that confer serotype; more than 90 pneumococcal serotypes have been identified, although a limited number cause most disease. Pneumococcal disease is the leading bacterial cause of pneumonia in children and also causes meningitis and septicemia. The CFR of pneumococcal disease worldwide is approximately 5 percent (range 4 percent to 9 percent), but it is more than double that rate in Sub-Saharan Africa (CFR 11 percent; range 7 percent to 18 percent) (O’Brien and others 2009). About 90 percent of pneumococcal deaths are due to pneumonia. Pneumococcal meningitis, though rare, has a higher CFR of 59 percent (range 27 percent to 80 percent); it can be as high as 73 percent in Sub-Saharan Africa. Before widespread pneumococcal conjugate vaccination, pneumococcus caused an estimated 826,000 deaths (O’Brien and others 2009) in 2000, and 541,000 deaths among children younger than age five years worldwide in 2008 (WHO 2013b).

Pneumococcal conjugate vaccines are at least 80 percent effective against meningitis, septicemia, and bacteremic pneumonia (Lucero and others 2009); like Hib vaccines, pneumococcal conjugates likely have reduced efficacy in HIV-infected children (Klugman and others 2003). Two pneumococcal conjugate vaccines are currently commercially available; one contains the conjugated polysaccharides of 10 serotypes, and the other contains 13 serotypes. Evidence suggests that declines in disease caused by vaccine serotypes with pneumococcal conjugate vaccine use may be partially offset by increased disease due to nonvaccine serotypes (referred to as serotype replacement); however, according to one meta-analysis of invasive pneumococcal disease in high-income countries, childhood vaccination resulted in 50 percent reductions in pneumococcal disease overall, despite some serotype replacement (Feikin and others 2013). Introduction of pneumococcal conjugate vaccine into Asian countries has lagged Gavi-supported introduction into Africa.

Rotavirus Vaccine

Rotavirus, a member of the reovirus family, causes watery diarrhea that can lead to dehydration and death. It is the leading cause of childhood diarrhea-related mortality worldwide (Parashar and others 2003), responsible for an estimated 453,000 deaths in 2008 (Tate and others 2012). Rotavirus accounts for 35 percent to 50 percent of acute severe diarrhea in children, varying by region (Mwenda and others 2010), with the highest proportions in children younger than age one year (Kotloff and others 2013). Unlike bacterial and parasitic causes of diarrhea, the occurrence of rotavirus diarrhea is not higher in settings with poor water, sanitation, and hygiene. A recent study of moderate-to-severe diarrhea in seven low-income settings found a CFR from rotavirus presenting to a health facility of 2.5 percent (Kotloff and others 2013). This figure is higher in areas without good access to health care (Feikin and others 2012) (see Keusch and others 2016, chapter 9 in this volume).

Two rotavirus vaccines are commercially available (WHO 2009). Both have been efficacious in randomized controlled trials in low-income settings, with efficacies generally ranging from 50 percent to 80 percent against rotavirus diarrhea; the lowest efficacy was seen in lower-socioeconomic, higher-mortality countries (Armah and others 2010; Madhi and others 2010). Nonetheless, because of higher rates of disease in these countries, the number of serious rotavirus infections prevented is likely to be higher, and the WHO strongly recommends rotavirus vaccine use in these countries (WHO 2009). Lower-cost rotavirus vaccines are still needed (Bharat Biotech 2011). Infants who receive rota virus vaccines have a slightly elevated risk of a rare but serious condition called intussusception, which can result in potentially fatal bowel obstruction, although increased incidence of intussusception is small relative to the overall impact of the vaccine (Patel and others 2012; Patel and others 2011). Future needs include development of vaccines with improved efficacy in high-burden countries and introduction of rotavirus vaccine into high-burden Asian countries.

Rubella Vaccine

The rubella virus, a member of the togavirus family, is one of the most teratogenic viruses known. In the absence of vaccination, rubella is a common cause of febrile rash illness in children, often misdiagnosed as measles. Infection of susceptible women early in pregnancy can result in miscarriage, fetal death, or a constellation of congenital defects known as congenital rubella syndrome (CRS) in up to 90 percent of infected infants. The incidence of rubella and CRS has been reduced in many high-burden countries following implementation of rubella vaccination strategies.

The goal of rubella vaccination in high-burden countries is to prevent the substantial disease burden associated with CRS. It is estimated that more than 100,000 CRS cases occur worldwide each year (Vynnycky, Gay, and Cutts 2003). Through 2013, 137 countries have included rubella-containing vaccines in national immunization schedules; the introduction of rubella vaccination in Asia and Sub-Saharan Africa lags other regions (WHO 2011b). Live-attenuated rubella virus vaccines were first licensed in 1970, but they were not included in EPI programs because of concerns that suboptimal vaccine coverage could delay age at natural rubella virus infection and result in higher incidence among women of childbearing age, paradoxically increasing the risk of CRS. Since 2011, the WHO has recommended introduction of rubella vaccination strategies as part of measles control and elimination activities, taking advantage of the availability of combined measles-rubella (MR) and measles-mumps-rubella (MMR) vaccines (WHO 2011b).

The preferred strategy for the introduction of rubella vaccination is to begin with MR/MMR vaccine in a campaign targeting a wide range of ages, in combination with universal childhood vaccination (Reef and Plotkin 2013). The first dose of combined MR vaccine can be delivered at age 9 months or 12 months, depending on the level of measles virus transmission (WHO 2011b). The effectiveness is at least 95 percent, even at age 9 months; only one dose of rubella vaccine is required to achieve rubella elimination if high coverage is achieved (WHO 2011b).

Meningococcal Meningitis Serogroup A Conjugate Vaccine

Neisseria meningitidis, also referred to as the meningococcus, is a Gram-negative encapsulated bacterium transmitted by respiratory droplets that can cause severe bloodstream infections and meningitis; it is the leading cause of bacterial meningitis in many LMICs. Explosive outbreaks of meningococcal meningitis occur with high attack rates and case fatality across broad age ranges. Six N. meningitidis serogroups (A, B, C, W, X, Y) cause almost all cases, although prevalence varies temporally and geographically. Sub-Saharan African countries from Senegal to Ethiopia in a zone referred to as the meningitis belt have experienced frequent and devastating epidemics of meningococcal meningitis, most often caused by serogroup A meningococcal strains. From 1993 to 2012, countries in the meningitis belt reported nearly 1 million meningitis cases, including 100,000 deaths (WHO 2013f).

Meningococcal vaccines prevent diseases caused by specific serogroups: vaccines against serogroups A, C, W, and Y contain purified polysaccharide alone or conjugated to carrier proteins (based on diphtheria or tetanus toxoids), while serogroup B vaccines contain outer membrane vesicles extracted from outbreak strains with the addition of recombinant proteins. Conjugate vaccines provide better long-lasting immunity, particularly in children younger than age two years, and indirect protection of unvaccinated groups through the reduction of disease transmission. Meningococcal conjugate vaccines have been introduced into routine immunization programs in many high-burden countries. In 2010, a serogroup A meningococcal conjugate vaccine developed by the Meningitis Vaccine Project, with funding from the Bill & Melinda Gates Foundation, was licensed for use in countries in the meningitis belt (LaForce and Okwo-Bele 2011). In the Sub-Saharan African meningitis belt, the WHO recommends mass vaccination of the population ages 1–29 years (WHO 2011a), a highly effective strategy for prevention of serogroup A meningococcal disease (Novak and others 2012), followed by routine childhood vaccination with a single dose at age 9–18 months (WHO 2015b).

Yellow Fever Vaccine

Yellow fever is a viral hemorrhagic fever that was one of the most feared epidemic diseases in the world before vaccination. Despite the availability of an effective vaccine, yellow fever continues to cause an estimated 84,000 to 170,000 severe cases annually, with 29,000 to 60,000 deaths (WHO 2013e). Most reported cases and deaths occur in 31 endemic Sub-Saharan African countries with a total population of 610 million, more than 33 percent of whom live in urban settings. Since the 1980s, yellow fever has reemerged in some areas or appeared for the first time in others.

Yellow fever vaccines contain live-attenuated virus and have been used since the 1930s (Monath and others 2013). Routine infant immunization against yellow fever is only recommended in 44 at-risk countries and territories, of which 35 included yellow fever vaccine in their routine infant immunization schedules in 2013. A single dose of yellow fever vaccine at age nine months or later is assumed to provide lifelong immunity.

Japanese Encephalitis Vaccine

Japanese encephalitis (JE) is the most common cause of viral encephalitis in Asia (WHO 2013c). JE virus, a flavivirus, is transmitted by mosquitoes in natural cycles involving domestic pigs or water birds; human disease is common in areas with rice cultivation and pig farming. Of the estimated 67,900 annual cases in the 24 endemic countries, 51,000 (75 percent) occur in children ages 0–14 years, resulting in about 10,000 deaths and 15,000 cases of long-term neuropsychiatric sequelae (Campbell and others 2011). Reported cases underestimate geographic distribution of risk because of underreporting and occurrence of disease in less than 1 percent of human infections (Halstead, Jacobson, and Dubischar-Kastner 2013). In recent decades, outbreaks have occurred in several previously nonendemic areas.

The WHO recommends the introduction of JE immunization through EPI programs in areas where JE constitutes a public health problem (WHO 2006a). In 2012, JE vaccines were used in immunization programs in 11 (46 percent) of 24 at-risk countries (WHO 2013c). The most effective strategy for controlling JE has been to conduct wide age-range (catch-up) vaccination followed by routine infant immunization. In upper-middle- and high-income economies—including Japan; the Republic of Korea; and Taiwan, China—routine immunization since 1965 using inactivated, mouse-brain-derived vaccine has successfully controlled the disease (Halstead, Jacobson, and Dubischar-Kastner 2013). However, disadvantages of the mouse-brain vaccine include the need for multiple doses, frequent boosting, and high prices (WHO 2006a). In 2013, the WHO and the United Nations Children’s Fund approved a live-attenuated JE vaccine from a Chinese manufacturer based on the SA 14-14-2 strain, which induces protection for several years after one or two doses (WHO 2013g). Approval of the live-attenuated JE vaccine should increase access in endemic countries.

Malaria Vaccine

Approximately 198 million malaria cases and 584,000 malaria deaths occurred globally in 2013; most deaths were in young children living in Sub-Saharan Africa (WHO 2015c). Plasmodium falciparum is the most virulent of the five Plasmodium species that cause human malaria. The RTS,S/AS01 candidate malaria vaccine is a partially effective vaccine that targets the pre-erythrocytic stage of the P. falciparum parasite resulting in a reduction in the number of clinical malaria episodes experienced. RTS,S/AS01 recently underwent testing in a large phase 3 clinical trial, the final stage before licensure. In total, 15,460 children and young infants participated in the trial, which was conducted at 11 sites in seven Sub-Saharan African countries across a wide range of malaria transmission levels (RTS,S Clinical Trials Partnership 2015). Among children ages 5–17 months at first vaccination followed for a median of 48 months, RTS,S/AS01 vaccine efficacy against clinical malaria was 37 percent (95 percent confidence interval 32–41) when the primary vaccination series of three doses administered monthly was followed by a booster given 18 months after the primary vaccination series, and 28 percent (95 percent confidence interval 23–33) when no booster was given. Vaccine efficacy was lower in young infants who received the primary vaccination series coadministered with EPI vaccines beginning at ages 6–12 weeks: 26 percent (95 percent confidence interval 20–32) with a booster and 18 percent (95 percent confidence interval 12–24) without. Despite modest efficacy estimates, the impact was substantial: 1,774 cases of clinical malaria were averted per 1,000 children vaccinated when a booster was administered; 1,363 cases were averted without a booster. The number of cases averted per 1,000 young infants was 983 in those who received a booster and 558 in those who did not. Meningitis and febrile seizures were reported more frequently in those who received the RTS,S/AS01 primary vaccination series than in those in the comparator group.

In July 2015, the European Medicines Agency issued a positive scientific opinion on RTS,S/AS01 for the prevention of malaria in children in Sub-Saharan Africa. Subsequently, the WHO’s Strategic Advisory Group of Experts on Immunization and the Malaria Policy Advisory Committee reviewed the evidence on RTS,S/AS01 efficacy and safety as well as other relevant information surrounding vaccine implementation. In October 2015, the WHO advisory groups recommended the implementation of the vaccine through pilot projects designed to better understand how well the vaccine can be implemented and to further assess the relationship of safety signals to the vaccine (WHO 2015d). The WHO is considering these recommendations and was expected to provide guidance in early 2016. RTS,S/AS01 may become the first malaria vaccine licensed for use in children in Sub-Saharan African countries (RTS,S Clinical Trials Partnership 2015).

Influenza Vaccine

Influenza viruses are orthomyxoviruses that cause respiratory illness, ranging from mild febrile illness to severe pneumonia. Because influenza viruses change rapidly, vaccines are reformulated and delivered annually through routine immunization or seasonal campaigns. Influenza viruses infecting humans are transmitted person to person, mostly by droplets and aerosols from the respiratory secretions of infected people. Influenza viruses cause seasonal influenza epidemics, mostly in the winter months in temperate climates, with less distinct seasonality in the tropics. Influenza has an annual attack rate of 5 percent to 10 percent in adults and 20 percent to 30 percent in children. When complicated by subsequent bacterial pneumonia, influenza infections can have high mortality rates. In general, the role of influenza in LMICs has been underestimated. A review suggests that 6.5 percent of hospital admissions for respiratory illness among Sub-Saharan African children were due to influenza (Gessner, Shindo, and Briand 2011). Another meta-analysis estimates that 28,000 to 111,500 influenza-associated deaths occur annually in children, with 99 percent occurring in LMICs (Nair and others 2013).

Licensed influenza vaccines include inactivated or live-attenuated influenza type A and B viruses. Inactivated influenza vaccines (IIVs) are administered by injection; live-attenuated virus vaccines are delivered as nasal spray. Only IIV is licensed for children younger than age two years. Two doses of influenza vaccine given four weeks apart are recommended during the first season a child is vaccinated. Vaccine effectiveness varies annually according to protection provided against circulating influenza viruses, but in general, vaccination has provided significant protection in children (Jefferson and others 2012), although few studies of vaccine effectiveness have been conducted among children in LMICs (WHO 2012b). Maternal influenza immunization has gained support as a way of protecting infants too young to be vaccinated against influenza disease. A study in Bangladesh shows that giving influenza vaccine to pregnant women led to an efficacy of 63 percent against lab-confirmed influenza and 29 percent against febrile respiratory illness in their infants’ first six months of life (Zaman and others 2008). Maternal influenza vaccination with IIV is now recommended in some countries and is being studied in LMICs as a method for preventing influenza in young infants (CDC 2013; WHO 2012a). No cost-effectiveness data on the use of influenza vaccine in LMICs are available. The WHO suggests that countries make their respective decisions on influenza vaccines based on local disease burden, resources, capacity, and other health priorities (WHO 2012a).

Oral Cholera Vaccine

Cholera is caused by ingestion of toxigenic serogroups (O1 and O139) of Vibrio cholerae bacteria, leading to diarrhea, dehydration, and rapid death. Periodically, new strains of V. cholerae emerge to cause pandemics. In 1970, the seventh pandemic strain appeared in Sub-Saharan Africa, where it is now endemic and accounts for the majority of cholera mortality (Mintz and Guerrant 2009). Cholera incidence and mortality is greatest in children (Ali and others 2012; Deen and others 2008), who account for 50 percent of all cholera deaths. Globally, cholera kills at least 45,000 children under age five years annually; this number is likely to be twice as high when considering out-of-hospital mortality (Ali and others 2012; Sack 2014). In 2010, cholera was introduced into Haiti following a massive earthquake, causing more than 500,000 cases (Barzilay and others 2013). Although the cholera CFR can be less than 1 percent in settings with good access to health care and proper treatment, these conditions rarely exist in most LMICs, where CFRs often exceed 5 percent and can be as high as 50 percent during outbreaks (Gaffga, Tauxe, and Mintz 2007; WHO 2010a).

There are two WHO-approved oral cholera vaccines, which contain formalin-inactivated or heat-killed whole-cell V. cholerae. One vaccine showed greater than 80 percent effectiveness against cholera for at least the first six months after administration (Clemens, Sack, and Ivanoff 2001; van Loon and others 1996); the second showed 67 percent effectiveness against cholera during the first two years of follow-up among children vaccinated at ages 1–4 years (Sur and others 2011).

These vaccines were cost-effective in a crowded city like Kolkata, India, at US$1 per dose; they would likely be cost-effective in other settings, such as Sub-Saharan Africa, if significant herd protection occurs with the vaccine, as has been hypothesized. In 2010, the WHO recommended use of oral cholera vaccines in addition to other preventive strategies, such as provision of safe water, in cholera-endemic countries or areas likely to experience outbreaks, with priority for vaccination given to children in settings of limited vaccine supply (Jeuland and others 2009; Longini and others 2007; WHO 2010a). For vaccination during large outbreaks like those in Haiti and Zimbabwe (Ahmed and others 2011; Barzilay and others 2013), the WHO plans to create an emergency stockpile of 2 million doses of cholera vaccine (Martin, Costa, and Perea 2012).