Anthrax V accine 1 Anil Chawla, Rakesh Bhatnagar Anthrax is caused by B. anthracis , a Gram-positive, spore-forming, rod-shaped bacterium that primarily infects herbivores such as cattle and deer . 1,3 The blood of an animal that dies of anthrax can contain upto 10 9 vegetative bacteria per millilitre. As the carcass decays, the bacteria form highly infectious endospores, which contaminate the local environment and can remain viable for long time periods. When spores are introduced into the body of a non-immune animal, they germinate, causing infection and death, thus completing the infectious cycle. Anthrax in humans, is rare and occurs mainly in individuals who come into close contact with farm animals or contaminated animal products such as wool or hides. Animals acquire B. anthracis infection via exposure to contaminated soil, where the organism persists in spore form. Animals also acquire infection from biting insects. Af fected animals develop a bleeding diathesis as manifested by bleeding from the nose, vagina and anus. These diseased animals die suddenly after the infection. B. anthracis has gained recent notoriety as a potential biological weapon because it can be easily dispersed by aerosols to produce inhalational disease. Apart from cases associated with its use as biological agent, human cases of anthrax result from exposure to infected animals or contaminated animal products, including: hides, raw meat, hair and bone meal. B. anthracis owes its lethality to two major virulence factors: an anti-phagocytic poly/-D- glutamic acid capsule and a toxin. 4-6 The toxin, discovered in the 1950s, consists of three proteins: protective antigen (P A; 83 kDa), lethal factor (LF; 90 kDa), and oedema factor (EF; 89 kDa). Individually , none of the three is toxic, but a mixture of P A and LF (called lethal toxin; LeTx) can cause lethal shock in experimental animals, and a mixture of P A and EF (called edema toxin; EdTx) induces oedema at the site of injection. The term binary toxin has been applied to such bacterial toxins when two discrete proteins must be combined to elicit toxicity . Genes encoding the three anthrax toxin proteins reside on a large plasmid (pXO1), 7 and those for capsule synthesis, on a different plasmid (pXO2). 4 Strains of B. anthracis carrying either plasmid alone are essentially avirulent, implying synergy between the two types of virulence factors. The importance of the toxin in infection and pathogenesis is further substantiated by the fact that immunization against it is protective. 8 The P A is the most immunogenic component of the toxin, hence its name. Anthrax as Bioterr orism W eapon In a simplistic way , it is possible to grow bacteria, let them form spores and just spray a spore solution over an enemy . Alternatively , the spore solution could be dried and used as a powder . It has always been a potential fear that terrorists may use anthrax either in spray form or powder form. W et dispersal When a solution is sprayed, the particle or droplet size tends to be quite large.

2 Cholera V accines S.K. Bhattacharya, Reeta Rasaily Infectious diseases are important causes of morbidity and mortality , particularly in the developing world. According to an estimate, 1 of the 1.12 crore deaths worldwide annually in children under five years of age due to infectious diseases, acute respiratory infections (18%) followed by acute diarrhoeal diseases (15%) are the two major causes of death. Acute diarrhoeal diseases are caused by a large number of pathogens including cholera caused by V . cholerae O1 and O139. 2,3 Cholera is acute infectious diarrhoea manifested by acute watery diarrhoea and vomiting leading to life-threatening dehydration which may cause death of the patient, if not treated promptly and adequately . In the developed countries, improvement of sanitation and personal hygiene and safe water supply has resulted in virtual disappearance of cholera, while the disease continues to take a major toll of morbidity and mortality . Cholera is endemic in many regions and occurs as sporadic, epidemic and pandemic forms. After 100 years of absence from Latin America, cholera invaded the continent and was responsible for major outbreaks. 4 Since major preventive measures are difficult to achieve in near future and cholera continues to be a major problem, vaccination against cholera is an attractive diseases prevention strategy . Pathophysiology V . cholerae O1 or O139 when ingested with food and water and is able to pass the gastric acid barrier in the stomach facilitated by the toxin co- regulated pillus (TCP) colonizes the small intestine where it multiplies and produces a toxin known as cholera toxin (CT). The CT has got two subunits; the B-subunit attaches to the receptor GM1 ganglioside, while the A1 of the A-subunit enters the enterocytes and the A2 stabilizes whole molecule. This excites a series of biochemical changes in the enterocytes resulting in outpouring of huge amount of fluid and electrolytes (Na + , K + , HCO3 - , and Cl - ). At a time when the outpouring of fluid and electrolytes exceeds the absorptive capacity of the large intestine, watery diarrhoea ensues. In fact studies have shown that the colon is also in a secretary phase. There is practically no structural damage in the gut mucosa in cholera . 5 Dehydration is the net result of this loss of fluid and electrolytes from the body in vomiting and diarrhoeal stools. Besides CT , a number of other toxins, such as, Zonula occludence toxin (ZOT), haemolysin, accessory cholera enterotoxin (ACC) are elaborated by V . c holerae. Immunity in Cholera Natural infection with V . cholerae provides protection for at least three years as this is, the longest period of available patient follow-up. There are two types of immune response seen in natural infection; the anti-toxic antibody and the antibacterial antibody . The latter antibodies are protective in nature and these vibriocidal antibodies are considered to correlate as surrogate markers of protection.

Dengue V irus V accines 3 U.C. Chaturvedi Dengue fever and dengue haemorrhagic fever (DHF) are caused by dengue virus (DV) of which there are four serotypes (DV 1 to 4). 1 Dengue fever is transmitted by Aedes aegypti mosquito which breeds in clean water found in discarded tires, uncovered water storage tanks, buckets, flower vases or pots, cans, cisterns, air coolers, air conditioners, among others. Dengue is the most common arboviral disease of humans and is found in subtropical and tropical areas of the world located Figure 1: Clinical pr esentation of dengue fever . Once DV r eaches its tar get cell, a cascade of events generally star ting with the interaction of viral envelope glycoproteins with specific entry receptors and co-receptors is necessary in order to trigger the virus-cell membrane fusion. The DV enters dendritic cell/macrophage through a virus receptor or the Fc-receptor as an immune complex. The DV replicates in local dendritic cells following inoculation into the skin by feeding virus-infected mosquito. The DV infection may be asymptomatic if further replication of the virus is inhibited by the innate response. After overcoming the innate immunity the virus subsequently spreads to macrophages and lymphocytes. This leads to entry of the virus into the bloodstream producing variable degree of viraemia in patients of all ages and that heralds the onset of clinical infection. It produces a milder self-limiting disease, the dengue fever (DF) or a severe disease, the dengue haemorrhagic fever/ shock syndrome (DHF/DSS).

Diphtheria, T etanus and Acellular Pertussis V accines: S tatus in Adults 4 Subhash V arma, Molly M. Thabah W ith the introduction of the DTP (diphtheria, tetanus and pertussis) vaccine more than 70 years ago, the incidences of these diseases fell down drastically . Diphtheria and tetanus are now rare diseases in the western world, although one still encounters cases in a country like ours. One has to be alert and consider such possibilities whenever the clinical situation arises. This especially applies to the fresh medical graduates and young physicians who would have only read and not encountered a case. Pertussis cases, although remarkably few compared to the pre-vaccination era, continue to occur causing maximum mortality in infants and morbidity in adults. The Centers for Disease Control (CDC), Atlanta and the Advisory Committee on Immunization Practice (ACIP) in the United States of America (USA) have released guidelines on the use of a single dose of tetanus toxoid, low antigen content diphtheria and acellular pertussis (Tdap) in adults as booster . In this chapter the basis for immunization against diphtheria, tetanus and pertussis in the Indian context along with vaccines available will be detailed and recommendations that can be applied to adults in India will be presented. Diphtheria In the pre-vaccination era, diphtheria was a leading cause of morbidity and mortality among children. Most children acquired immunity by natural infection and only 15% of these infections were symptomatic. 1 Forty percent of the case occurred in children below the age of 5 years and 70% below the age of 15 years. Therefore in the pre-vaccine era circulation of C. diphtheriae was frequent and immunity was acquired by apparent or inapparent infection. W idespread circulation of the toxigenic strain ensured that adults had frequent boosting of their natural immunity and that made the disease rare in adults. 2 V accine Era Diphtheria toxoid (DT) was introduced as part of routine immunization in the 1940s and 1950s in the industrialized nations which led to a marked decline in the incidence of diphtheria. 2 W idespread vaccination coverage has led to reduced circulation of toxigenic strain, which in turn has led to less boosting of natural immunity in adults, making them susceptible to the disease. In India diphtheria is endemic. India has witnessed a drop in reported cases from 39,231 in 1980 to 3,354 in the year 2007; however , in the year 2005, 10,231 cases were reported from India to the W orld Health Or ganization (WHO) and constituted 80% of the disease burden. 3 This report may still be an underestimation due to lack of systematic surveillance system our country . Though sporadic outbreaks have been reported, yet the exact incidence of diphtheria in our country is still unknown. 4-6 In India, the available published data on diphtheria are retrospective case series from individual hospitals and majority of cases have been children below the age of 5 years. 7-13 A recent study from Hyderabad showed an increase in annual incidence of diphtheria from 11/100,000 to 23/100,000 from 2003 through 2006. Most of these cases occurred in children 5 to 19 years of age. This study also reported that coverage for primary vaccination, fourth and fifth dose of DPT vaccine was 90%, 60% and 33% respectively .

Haemophilus influenzae T ype b V accine 5 Nitin Shah Haemophilus influenzae type b (Hib) infection along with pneumococcus is one of the most common causes of invasive bacterial infection in less than 5 years old children. Mass vaccination against Hib has led to virtual elimination of the disease from countries like Finland, United Kingdom (UK), the United S tates of America (USA), etc. 1,2 I n developing countries like India, it is still a major cause of meningitis and pneumonitis as these countries can not afford to include this vaccine in the National Immunization Program. However , Global Alliance for V accine Implementation (GA VI) has pledged to help developing countries to include newer childhood vaccines like Hib in the National Immunization Program by offering these vaccines at higly subsidized cost. Hence, there is an urgent need to establish the disease burden in such countries so that respective governments can make use of this incredible help from GA VI. Epidemiology Pathogen H. influenzae capsule is made of polyribosyl ribitol polysaccharide (PRP) and based on the capsular PRP H. influenzae is further divided in to six types (a-f). Among the six subtypes, type b (Hib) is the most dreaded organism as it leads to invasive disease. 95% of invasive disease due to H. influenzae occurs due to type b whereas only 5% disease burden is due to type a or other non-typable H. influenzae organisms. Host Majority (95%) of Hib infection occurs in children under 5 years of age with a peak occurring at 6 to 18 months of age. Non-type b H. influenzae usually causes upper respiratory infection and rarely invasive disease. 3,4 Risk factors for Hib infection include poor socio-economic conditions, over crowding, day care centres and certain high risk diseases like diseases like asplenia, sickle cell anaemia, splenectomy , immunodeficiency states, nephrotic syndrome, complement deficiency . 2 Morbidity Infection with Hib leads to a spectrum of clinical manifestations starting from asymptomatic carrier state to various types of invasive diseases including meningitis, pneumonia, epiglottitis, bacteraemia, skin infections and, bone infection. It is estimated that every year there occur 3 million cases of Hib infection of which there are 0.375 million deaths. Studies from west have indicated an annual incidence of 50 to 100/100,000 under 5 year old children. 2,5 Nearly 50 to 60% of total Hib infection presents as meningitis, 5% to 8% each as pneumonitis, epiglottitis, skin infections, bone infections and bacteremia. Data from developing countries like India is meager; the incidence varies from 100 to 250/100,000 in children under 5 years of age. Majority of them present as meningitis (70- 90%) or pneumonitis (10-20%). Epiglottitis and skin infection of face are rarely observed in developing countries as most develop Hib infection very early in life leading to invasive disease. 2,5 In India only hospital based data is available as shown in T able 1.

6 Hepatitis A V accine Premashish Kar , Rajiv Singla Hepatitis A vaccine has been in clinical use for last thirteen years. The inactivated hepatitis A vaccine [Havrix (GlaxoSmithKline, Rixensart, Belgium)] was first licensed for use in 1995 and a second product [V aqta (Merck & Co Inc, Whitehouse S tation, New Jersey)] in 1996, after approval from the United S tates Federal Drug Authority (FDA). Both preparations were initially licensed to be used in children of age more than two years. As incidence of hepatitis A started to decline due to herd immunity induced by the vaccine, it was recommended for use in people belonging to specific high-risk groups, including children, two years and older who live in defined and circumscribed communities with high endemic rates or periodic outbreaks; people with chronic liver disease; men who have sex with men (MSM); illicit drug abusers; and people with occupational hazards that put them at increased risk of acquiring hepatitis A. 1 Although hepatitis A i s mostly self-limiting and rarely fatal, the disease may represent a substantial economic burden, particularly in countries with low and intermediate incidence rates. In India, recommendation for hepatitis A vaccination is complicated by certain epidemiological issues. High incidence and prevalence of hepatitis A leads to early and asymptomatic infection in children. A s most of school-going children in high prevalence areas have protective antibody and high cost involved, consensus for routine vaccination for hepatitis A is lacking. But indications for vaccination in adults are undisputed and are same in India and western world. The goals of hepatitis A immunization are to protect persons from infection, reduce the incidence of disease by preventing transmission and ultimately eliminate transmission. Children should be the main focus of immunization strategies because of their high incidence of disease and critical role in disease transmission. Routine vaccination of children would result in the following: Prevention of infection in age groups that account for at least one third of hepatitis A virus (HA V) infections; elimination of a main source of infection for other children as well as adults; and eventual prevention of infection in all older persons as children who have been vaccinated become adults. The immunity induced by the vaccine is probably long-lasting. 2 Epidemiology The virus has a worldwide distribution and causes about 15 million cases of clinical hepatitis each year . 3 Prevalence of infection varies considerably depending on hygiene and sanitation conditions. In areas with overcrowding, limited access to clean water and inadequate sewage systems, hepatitis A infection occurs almost universally in people early in life. Because most young children who acquire hepatitis A are asymptomatic, disease rates in highly endemic areas of the world are low . 4 Although seronegative adults in such areas of the world are at high risk of infection and disease, outbreaks are unusual because of the high prevalence of antibody to HA V in the population. 5 For practical purposes, the world can be divided into areas of low , intermediate and high disease endemicity , although there may be regional differences in endemicity within a country . In areas of low endemicity the disease occurs mainly in adolescents and adults in high risk groups (e.g.

7 Hepatitis B V accination Manoj Kumar , Shiv K. Sarin Hepatitis B virus (HBV) causes a spectrum of liver disease, including acute self-limited hepatitis, acute fulminant hepatitis and chronic HBV infection. Potential sequelae of chronic infection include cirrhosis, hepatocellular carcinoma (HCC) and death. After HBV infection, asymptomatic seroconversion is common and the likelihood of developing acute hepatitis is age dependent. Perinatal HBV infection is almost always asymptomatic, whereas 5 to15% of children 1 to 5 years of age and 33 to 50% of older children, adolescents and adults develop acute hepatitis after HBV infection. The likelihood that a newly infected person will develop chronic HBV infection is also dependent on the age at the time of infection. More than 90% of infected infants, 25 to 50% of children infected between 1 and 5 years of age and 6 to 10% of acutely infected older children develop chronic infection. Immuno suppressed persons are also more likely to develop chronicity . Universal vaccination can prevent most acute HBV infections. However , in India the status of universal vaccination is a contentious issue, thus HBV remains a major concern. Burden of HBV Infection in India HBsAg prevalence rates among blood donors has varied from 1 to 6% and from 2.6 to 9.5% among pregnant women. Community data on HBsAg and anti-HBs positivity in the Indian population are scarce. However , among studies in healthy individuals, the HBsAg and anti-HBs positivity has been reported to be 1.6 to 2.1% and 17.1 to 19.5%, respectively . 1 The HBsAg positivity rate of Hepatitis B in India is different in the different regions of the country . The overall chronic HBsAg positivity rate is often quoted as being 4.7%. 1 This is the weighted mean of various studies and includes high risk populations. Lodha et al 2 did a systematic review of literature and concluded that the true prevalence of Hepatitis B in India was 1 to 2%. A recent meta- analysis found the true prevalence in non-tribal populations is 2.4% [95% confidence intervals (CIs): 2.2-2.7] and among tribal populations is 15.9% (95% CIs: 1 1.4-20.4). 3 Recently , studies have shown that within India hyperendemic regions for HBV infection may exist in tribal populations with HBsAg prevalence reaching upto 23%. 4 A comprehensive strategy to eliminate HBV transmission includes (i) universal vaccination of infants beginning at birth; (ii) prevention of perinatal HBV infection through routine screening of all pregnant women for hepatitis B surface antigen (HBsAg) and post-exposure immunoprophylaxis of infants born to HBsAg-positive women or to women with unknown HBsAg status; (iii) vaccination of all children and adolescents who were not vaccinated previously; and (iv) vaccination of previously unvaccinated adults at risk for HBV infection. Hepatitis B vaccination is the most effective measure to prevent HBV infection and its consequences. Hepatitis B vaccination is recommended for all infants, older children and adolescents who were not vaccinated previously , and adults at risk for HBV infection. Among adults, ongoing HBV transmission occurs primarily among unvaccinated adults who are at risk for HBV infection.

8 Hepatitis E V irus V accine Pranav Gupta, S.K. Acharya, S.K. Panda Hepatitis E V irus (HEV) is an important aetiological agent of enterically transmitted hepatitis or water borne hepatitis. It is estimated to affect 2.2 million people per year in India alone and close to 6 million people per year traveling from non-endemic regions to the endemic zone 1 . It mainly affects adults with a low mortality rate (0.5-3%) except in pregnant women where it reaches upto 30% especially in third trimester . 2,3 However , recently it has been reported that severity of disease is independent of sex and pregnancy status of patients. 4 Over and above, recent reports indicate that, cirrhotics in hyperendemic area are also prone to contact HEV more often than healthy control and subsequent to HEV superinfection, these cirrhotics rapidly decompensates and die. 5,6 Therefore, protection against HEV specifically for pregnant females, cirrhotics in hyperendemic area and travelers to hyperendemic area and population at large during epidemics of HEV seems to be an urgent necessity . The HEV was first reported in Indian subcontinent when the first outbreak occurred in New Delhi during 1955-1956 due to contaminated drinking water . 7 Several such epidemics were subsequently identified in central and southeast Asia, the Middle East and North Africa. 8,9 In addition to epidemic hepatitis, HEV causes widespread sporadic infections in endemic areas. 10 The existence of a viral etiological agent for hepatitis E was first demonstrated in 1983 when spherical, non- enveloped 27 to 30 nm virus-like particles were visualized by immune electron microscopy in feces from a volunteer who was infected with stool from a non-A, non-B hepatitis patient. 10 The first complete genomic sequence of HEV was determined in 1991. 11 The HEV is a sole member of the genus Hepevirus in the family of Hepeviridae. 12 The viral genome is a single-stranded, positive-sense, capped, polyadenylated RNA molecule of approximately 7.2Kb with short 5and 3 untranslated regions (UTRs). It consists of three partially overlapping open reading frames (ORFs). ORF1 encodes the non- structural, enzymatically active proteins involved in virus replication and a probable role in viral protein processing. Putative functional motifs and domains such as methyltransferase, papain-like cysteine protease (PCP), helicase, and ribonucleic acid (RNA)- dependent RNA polymerase (RdRp) have been identified in ORF1. The ORF2 encodes a 660-amino acid capsid protein and contains important epitopes that can induce neutralizing antibodies. 11 ORF3 encodes a small-phosphorylated protein with unknown function and is associated with cytoskeleton. 13 The main mode of transmission of HEV is feco-oral although person to person transmission has also been reported. 14 V ertical transmission of HEV infection from mother to infant is also known to occur . 15 Not often but it can also be transmitted by transfusion of blood or blood products. 16,17 The sequence analysis indicated that there are four major genotypes of HEV : the genotype 1 (Asian and African HEV strains), the genotype 2 (the single Mexican HEV strain), the genotype 3 [human and swine HEV strains from industrialized countries, such as the United States of America (USA), Japan, Argentina and Europe], and the genotype 4 (human and swine HEV strains from Asia).

Human Immunodeficiency V irus V accine 9 Ramesh Paranjape, Meera Singh, Samir Lakhashe Since the discovery of smallpox vaccine by Edward Jenner in the year 1798 vaccines against different infectious diseases have helped mankind in saving millions of lives world over . V accine has proved to be a very important public health tool applied for the control of infectious diseases. Although there is no licensed prophylactic vaccine to either protect humans from human immunodeficiency virus (HIV) infection or a therapeutic vaccine to mitigate the course of disease progression intense efforts are on to search for such a vaccine. Pathogenesis and Immune Response The HIV infection passes through an acute primary HIV infection characterized by intense virus multiplication and activation of HIV -specific immune response followed by asymptomatic phase that is characterized by continuation of virus multiplication and steady erosion of immune system and lastly acquired immunodeficiency syndrome (AIDS) phase when immune system is destroyed and opportunistic infections and malignancies are seen frequently . The HIV -specific immune response is evident especially during early infection and among long-term non-progressors (L TNPs). These HIV infected individuals have been able to control virus multiplication efficiently and hence have low or undetectable virus load, stable CD4+ counts, strong HIV -specific immune response and they do not suf fer from opportunistic infections. Innate immune responses, HIV -specific helper and cytotoxic T -cell response and anti-HIV neutralizing antibody response are considered to be crucial in control of HIV based on the observations in long- term non-progressors and persons exposed to HIV infection but are not infected as well as studies among cohorts of HIV infected persons. These observations have also been supported by animal studies. Hence, there is a reason to believe that appropriate HIV -specific immune response may be able to prevent HIV infection or help in keeping virus load low among those infected to ensure that the disease progression is arrested, the infectivity reduced and quality of life improved. Obstacles for V accine Development Although pursuit for HIV vaccine started very soon after the first isolation of HIV virus, the vaccine efforts are confronted with some serious obstacles. One of the important limitations in the feasibility of HIV vaccine is the ability to protect against the genetic variants. Due to the presence of reverse transcriptase without proof reading ability HIV undergoes mutations during multiplication cycle. The variants many times escape from the immune system due to the difference in antigenic structure as a result of mutation. T o deal with the genetic variations, the researchers have attempted to concentrate on the conserved genes to minimize the impact of genetic variations. The other major barrier is the absence of suitable animal model. HIV cannot infect animal species other than humans and chimpanzees. However , due to various reasons using chimpanzee model is not practical. The third important barrier is lack of clear understanding of the correlates of protection.

Human Papillomavirus (HPV) V accine 10 Neerja Bhatla Human papillomavirus (HPV) is a non-enveloped deoxyribonucleic acid (DNA) papovavirus. Of the more than 100 different types of HPV identified, at least 30 have been found to infect the genital mucosa in humans. The HPV types have been divided as low- and high-risk depending on the type of lesions caused. Low-risk HPV types cause anogenital warts, of which HPV -6 and -1 1 are responsible for about 90%. 1 They have also been implicated in the development of recurrent respiratory papillomatosis (RRP). Persistent infection with high-risk HPV types has been shown to be an established cause of cervical cancer . 2 At least 15 high-risk genotypes are associated with various cancers, including cervical, vaginal, vulvar , penile, anal and oesophageal cancer ( T able 1). 3 Predominant among these are HPV - 1 6 and -18 that are responsible for 70% of cervical cancers. 4 T able 1: Association between HPV and cancer Cancer % association with HPV types Cervical* > 95 V aginal* 50 Vulvar* > 5 0 Penile 5 0 Anal > 7 0 Non-melanoma skin/ cutaneous squamous cell 9 0 * Includes cancer and intraepithelial neoplasia In immunocompromised patients HPV = human papilloma virus Burden of Disease HPV infection is one of the most common sexually transmitted infections. Nearly 80% of sexually active women and men are infected with HPV at some point in their lives. 5 W omen of all age groups are potentially at risk of HPV infection. 6,7 The majority of HPV infections are transient and asymptomatic and cause no clinical problems; 70% of new HPV infections clear within one year , and approximately 90% clear within two years. 8-10 The median duration of new infections is eight months. 8,9 Symptoms are produced only when clinically significant sequelae of HPV infection develop including cervical cancer and cervical cancer precursors, other anogenital cancers including vaginal and vulvar intraepithelial neoplasia, anogenital warts or RRP . The most important of these is undoubtedly cancer of the uterine cervix, the second most common cancer among women worldwide and the commonest in India. Approximately 5 lakh new cases of cervical cancer are diagnosed each year across the globe. In developed countries, systematic Pap smear based screening programs have helped control the disease by diagnosing and treating the precancerous stages, but in developing countries that have only opportunistic screening programs, women still present in advanced and incurable stages. Thus in India, there are an estimated 132,000 new cases and 74,000 deaths every year . 11 Although anogenital warts and RRP constitute lesser priorities as intervention targets, these diseases increase the morbidity burden associated with HPV .

Influenza V accine 11 V inay Gulati, Jaya Prakash Sugunaraj Influenza commonly known as the flu, is caused by ribonucleic acid (RNA) virus of the family Orthomyxoviridae. Influenza A and B are the two types of influenza viruses that cause epidemic human disease. Influenza A viruses are further classified into various subtypes based on two surface antigens: haemagglutinin and neuraminidase. Most of the infections are caused by influenza A (H1N1), influenza A (H3N2), and influenza B viruses which have circulated globally . Influenza A (H1N2) viruses that probably emerged after genetic reassortment between human A (H3N2) and human A (H1N1) viruses also have been identified in some influenza seasons. Both influenza A subtypes and B viruses are further separated into groups on the basis of antigenic similarities. Antigenic drift results from point mutations that occur during viral replication. 1 Frequent emergence of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and is the reason for annually reassessing the need to change one or more of the recommended strains for influenza vaccines. In comparison antigenic shift occur less frequently . Antigenic shift occurs when a new subtype of influenza A virus appears and can result in the emergence of a novel influenza A virus with the potential to cause a pandemic. New influenza A subtypes have the potential to cause a pandemic when they are able to cause human illness and demonstrate efficient human-to-human transmission and there is little or no previously existing immunity among humans. 1 Disease Burden Acute viral respiratory infections are the most common illnesses experienced by otherwise healthy adults and children causing a significant morbidity . Mortality due to acute viral respiratory illness in economically developed countries is less compared to the developing countries. Monthly incidence of respiratory infections is 23% in urban area and 17.7% in rural area. 2 Outbreaks of respiratory tract infections are also common in tertiary care centers for the aged. In a prospective longitudinal community-based study from north India, the virus specific incidence rates for acute respiratory tract infections (ARI) per 1000 child years were 141 for influenza A and 37 for influenza B.The study also found that respiratory syncytial virus (RSV), influenza A and parainfluenza virus 3 were important causes of ARI among children in rural communities in India. 3 Another study 4 looking at the pattern of respiratory viruses in an out-patient department (OPD) found that RSV was the most commonly observed (n = 100, 26%); followed by influenza viruses (n = 21, 5.4%); parainfluenza virus (n = 8, 2.1%); and adenovirus (n = 3, 0.8%). 4 Rates of infection are highest among children, but the risks for complications, hospitalizations, and deaths from influenza are higher among persons aged 65 years and older , young children, and persons of any age who have medical conditions that place them at increased risk for complications from influenza. 5 Estimated rates of influenza-associated hospitalizations and deaths varied substantially by age group in studies conducted during different influenza epidemics and most of the data were from the developed world.

12 Japanese Encephalitis Kaushik Bharati, Sudhanshu V rati Japanese encephalitis (JE) is the most important form of viral encephalitis in the world. This disease is so named because it was originally detected in Japan. The disease has now spread to most parts of South-East Asia, China, India, and even to far -of f places like Australia. JE virus (JEV), responsible for causing JE is an arthropod-borne virus belonging to the family Flaviviridae and genus Flavivirus. It is spread by the bite of infected Culicine mosquitoes , predominantly Culex tritaeniorhynchus and Culex vishnui . The major amplifying vertebrate hosts are domestic pigs . W ading and migratory birds are also involved in the transmission cycle. Man is an incidental host and viral titers are so low that further transmission does not occur . For this reason, humans are regarded as dead-end hosts. This is predominantly a disease of children living in rural areas, although people residing in suburban areas may also be af flicted. Approximately 50,000 cases of JE are reported annually , of which 10,000 prove to be fatal. Those who survive the disease are left with lifelong neurological and psychiatric problems. Therefore, JE, is a serious public health problem, even though its severity is often underestimated in literature. The control measures for JE may be two-pronged, namely vector control and prophylactic vaccination. Since the former has its limitations, it is the latter that has to be relied upon to keep the disease at bay . It should, however , be noted that unlike smallpox and polio, for which humans are the only host, JE is a zoonotic disease and hence cannot be eradicated from the face of earth. Moreover , since no specific antiviral therapy is currently available, vaccination is the mainstay for controlling this disease (T able 1). T able 1: J a panese encephalitis: Historical timeline 1870s First JE outbreak in Japan 1924 Isolation of JEV virus from a fatal case of encephalitis in monkeys 1935 I s o l a t i o n o f N a k a y a m a s t r a i n f r o m a f a t a l human case 1950 Elucidation of route of virus transmission 1955 First Indian JE cases in V ellore 1973 First Indian JE epidemic in Bankura 1990 JE spreads to Western and North Western India 2006 India imports SA 14-14-2 vaccine from China JE = Japanese encephalitis The Pathogen The disease causing agent Japanese encephalitis virus is a Flavivirus that is antigenically related to several other flaviviruses prevalent in Asia, including Dengue and W est Nile viruses. It is spherical and is approximately 50 nm in diameter . Its nucleocapsid core is surrounded by an envelope. Its single-stranded, positive sense RNA genome codes for a single polyprotein that is cleaved into 3 structural and 7 non-structural proteins. The structural proteins are capsid (C), envelope (E), and membrane (M). The non- structural proteins are NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. The envelope is the most important viral protein from vaccine development standpoint as it possesses most of the neutralizing epitopes that are targets for neutralizing antibodies forming the primary mediators of immunity .

Leishmania V accine 13 Kamlesh Gidwani, Madhukar Rai, Jaya Chakravarty, Shyam Sundar Leishmaniasis is caused by intracellular , protozoan parasites of the genus Leishmania transmitted by sand flies. There are three major forms of leishmaniasis in human viz. namely , cutaneous (CL), mucocutaneous (MCL) and visceral leishmaniasis (VL). Leishmaniasis is endemic in 88 countries, of which 72 are developing countries including 13 of the least developed countries. Nearly 90% of CL occurs in seven countries: Afghanistan, Algeria, Brazil, Iran, Peru, Saudi Arabia and Syria, while 90% of VL occurs in five countries- India, Bangladesh, Nepal, Sudan and Brazil. 1 It is estimated that 2 million new cases occur each year , with at least 12 million people presently infected worldwide and the burden of disease expressed in disability-adjusted life years (DAL Ys) is estimated to be almost 2 million years. 2 Also known as kala-azar , VL is a systemic infection of the reticuloendothelial system. The disease is characterized by fever , weight loss, hepato- splenomegaly and pancytopenia. Kala-azar is predominantly a disease of the poor in remote communities with few health care facilities. W ithout specific treatment, VL is almost always fatal and delayed treatment is associated with higher mortality . Current treatment for leishmaniasis includes pentavalent antimonials, amphotericin B, pentamidine, and Miltefocine. These treatments are expensive, have serious associated toxicities and may lead to the development of drug-resistant parasites. Therefore, safe, effective and economical vaccines are need of the hour . Immunology of Leishmania Infections The protective immune response to Leishmania is thought to be primarily cell-mediated. Each clinical manifestation of Leishmania infection has a different immunological profile. The patients with acute VL lack Leishmania-specific delayed type hypersensitivity (DTH) responses and lack T -cell proliferation responses to the parasite antigen in vitr o . However , recovery from VL is associated with the development of DTH and proliferative T -cell responses. 3,4 Patients with both active and cured CL have strong DTH responses and vigorous in vitro proliferative responses to Leishmania antigens. In contrast the uncontrolled cutaneous lesion of diffuse cutaneous leishmaniasis (DCL) is associated with the absence of a DTH response to leishmanial antigens. Mucosal leishmaniasis (ML) is characterized by hyper -reactive skin tests and T - lymphocyte proliferative responses possibly resulting in destruction of mucosal tissues and the paucity of parasite in these lesions. 5 Leishmaniasis and Leishmania V accine Leishmaniasis is considered to be one of a few parasitic diseases likely to be controlled with vaccination. The relatively uncomplicated leishmanial life cycle and the fact that recovery from infection renders the host resistant to subsequent infection indicate that a successful vaccine is feasible. Extensive evidence from studies in animal models indicates that robust protection can be achieved by immunization with protein or deoxyribonucleic acid (DNA) vaccines. However , to date no such vaccine is available inspite of the concerted efforts by the scientific community all over the world.

14 Lepr osy V accines V ishwa Mohan Katoch, Umesh Datta Gupt a Mycobacterium leprae discovered in 1872 by G .A.Hansen, was the first major bacterial pathogen of man identified as a causative agent of human disease, but till date, it is one the few human pathogens that could not be cultivated in any acceptable in-vitro medium system . M. leprae like M .tuberculosis is having general characteristics of Gram-positive bacteria and take acid-fast staining, a peculiar characteristic of all mycobacteria due to the presence of unusually high waxy lipid cell walls. In adults, leprosy has got a long latency of almost five years between putative infection and the manifestation of the disease due to which the mode of transmission remains unknown. During the last 25 years India has also achieved spectacular success in achieving more than 95% reduction in the burden of disease by massive coverage with multi-drug treatment (MDT). India reached the elimination levels more than two years ago. A total of 138,000 new cases were detected during the year 2007-08, which gives annual new case detection rate (ANCDR) of 11.7 per 100,000 population. A total of 87,000 cases in India are on record as on 1st April 2008 giving a prevalence rate (PR) of 0.74 leprosy cases per 10,000 population. 1 Despite major success in reducing the prevalence, the transmission of disease is continuing in some areas. 2,3 If such pockets persist after appropriate strategy and coverage, immunoprophylaxis could be one of the alternate approaches in moving towards ultimate eradication. The vaccines are generally prepared from killed or attenuated organisms that have lost the virulence but retain the protective antigens. In another approach, the live attenuated or killed non- pathogenic organisms that antigenically cross react with the pathogens are used. The third approach makes use of only the immunogenic subunit of the organism. There are clear cut indications that suggest that it should be practically feasible to develop vaccine either to prevent leprosy . The main assumption underlying the development of any vaccine against leprosy is that induction of sufficient level of cell mediated immunological reactivity to antigens of M .leprae will provide protection. The direct evidence establishing a relationship between immunity and protection derive from study of leprosy patients from different leprosy spectrum. The patients with tuberculoid disease can restrict M .leprae growth as they have high level of cell mediated immunity (CMI) while lepromatous patients failed to control the dissemination and growth due to poor CMI. The specific CMI can be induced by immunization with killed M. leprae and this concept gets support from re-interpretation of Mitsuda test, the common skin test used for leprosy . This test is specific for CMI as unlike other tests, it is read at 28 days .Though CMI can be detected in most systems by a test read at 48 hours including Fernandez test or the Dharmendra lepromin test, Mitsuda tests measures not only prevailing delayed type hyper- sensitivity (DTH) but acts as a weak vaccine. It discriminates individuals with lepromatous leprosy (non-responders) with those who have already been infected clinically or subclinically (responders). Thus Mitsuda test acts like a booster . The observation that good number of normal individuals belonging to leprosy non-endemic areas become Mitsuda-positive , indicating that either it is acting as vaccine or some of these individuals have come in contact with cross reactive mycobacterial antigens or other mycobacteria in the environment.

Immunization in Humans with Experimental Malaria V accines 15 V irander Singh Chauhan Malaria is a disease caused in humans by four species of parasites of genus Plasmodium , P. falcipar u m , P . vivax , P . ovale and P . malariae . Malaria is one of the major causes of mortality and morbidity worldwide, affecting nearly 40% of the world s population and accounting for about 3 to 5 million deaths and more than 500 million new cases annually . W ide spread resistance of the parasite to common and easily accessible drugs like chloroquine and insecticide resistance in the mosquito vector has made the malaria situation very alarming. 1,2 Therefore, much emphasis is being placed on the development of new antimalarial drugs and on the development of antimalaria vaccines. Research activity in these areas has received a much needed boost from the availability of the complete genome sequence of P . falcipar um , and more recently of P . vivax and P . knowlesi. 3,4 It is believed that among other strategies to combat malarial, a efficacious malaria will play a crucial role. There are two main bodies of evidence suggesting that eliciting protective immunity to malaria is achievable. First, the natural immunity to malaria develops in humans living in malaria endemic areas and also that a passive transfer of antibodies can provide protective immunity in humans. The second, immunization with irradiated sporozoites provides complete protection in animals as well as in humans. Malaria vaccine research field has been active and there are as many as 80 vaccine constructs which are at the preclinical development stage and many have entered clinical testing. 5 However , the progress in developing a useful malaria vaccine has been slow and no approved vaccine exists as yet for malaria. There are many hurdles in the path of development of malaria vaccines including complex multistage life cycle of the parasite involving complex invasion processes and incomplete knowledge the effective mechanisms involved in malaria immunity and a lack of suitable animal experimental models to test the efficacy of vaccine constructs and the lack of in vitro correlates of protection. Immunity to malaria takes several years of exposure to malaria infection and the acquired immunity is only partial ef fective and short lived. Further , the acquired immunity is also highly stage and strain-specific mainly because of the capability of the parasites to alter critical antigenic constructs rapidly . All these factors put together contribute to the development of malaria vaccines as a highly complex exercise. Besides these scientific problems, inherent to the nature of the disease, there are additional organizational hurdles like the general lack of expertise in good manufacturing practice (GMP) vaccine development in academic institutions involved in malaria vaccine research, non- availability of suitable adjuvants needed for subunit vaccine and extremely high cost of clinical trials. There are three distinct stages of the malaria parsite during its development cycle in the human host: the live stages (sporozoites), the erythrocytic or blood stages (merozoites) and the sexual stages (gametocytes) and during these stages different sets of proteins are expressed. Thus most vaccine development strategies have targeted specific malaria antigens from the three different stages resulting in stage specific vaccines. Malaria vaccine research and development has been the subject of excellent reviews from time to time.

16 MMR V accine Sanjay Jain, V ikas Suri V accines are among the most ef fective public health and medical strategies for protecting and preserving health. V accine recommendations are based on epidemiology and burden of diseases, vaccine characteristics and its safety , cost-ef fectiveness of the preventive measures, expert opinion of public health officials, expert clinicians and specialists in preventive medicine. The success of childhood vaccination programs has made a major contribution to the reduction and elimination of many childhood diseases worldwide. However , similar success has not been achieved in adults, and vaccine preventable diseases continue to be a significant cause of morbidity and mortality among adults. 1 This vaccination gap has many inherent reasons behind it, the prominent among them being limited appreciation of the importance of vaccine-preventable diseases by adult population, doubts about the safety and efficacy of an adult vaccine, lack of a universal approach as different target groups require different vaccine strategies, lack of public awareness or proper health programmes supporting adult immunization and lastly the finances involved in procuring vaccines. The magnitude of the problem can be judged from the fact that approximately 45,000 adults in the United S tates of Amercia (USA) die annually of complications from influenza, pneumococcal infections, and hepatitis B, the primary vaccine- preventable diseases affecting adults. The estimated total economic cost of treating these vaccine- preventable diseases among adults, excluding the value of years of life lost, exceeds $10 billion each year . 2 Although adults account for fewer than 5% of all cases of chickenpox (varicella), they are ten times more likely than children to develop serious complications, such as, pneumonia, sepsis, encephalitis and even death. Keeping these issues in mind the US Department of Health and Human Services launched Healthy People 2010 3 initiative in the year 2000, a comprehensive nationwide health promotion and disease prevention agenda, with special emphasis on adult immunization, the target being at least 90% coverage for annual influenza and pneumococcal vaccination among adults aged 65 years or above, 60% coverage with both vaccines among high-risk adults aged 18 to 64 years, 75% reduction in number of cases of h epatitis A and B and, lastly , elimination of diphtheria, measles, mumps and rubella (MMR) among adults. Considerable work is needed to achieve the above goals seeing the dismal vaccination rates of 66 and 50 % in the year 2000 for these two vaccines. 4 The Advisory Committee on Immunization Practices (ACIP) 5 recommended adult immunization schedule that provides vaccination recommendations for 14 vaccine-preventable diseases, tetanus, diphtheria, pertussis, human papillomavirus, measles. The recommended schedule also contains guidelines for administering vaccines to human immunodeficiency virus (HIV) infected adults. The recommendations are organized by vaccine, by medical and other indications, and by the CD4+ T -lymphocyte count as a measure of degree of immunosuppression. The rational and the risk benefit considerations for administration of MMR vaccine in adults will be reviewed in this chapter .

17 Meningococcal V accination Sunil Gupta, Smrita Singh, Shashi Khare, Shiv Lal Meningococcal disease is an acute bacterial disease caused by Gram negative capsulated diplococcal bacteria, the meningococcus ( Neisseria meningitidis ). Meningococci are classified by serological typing on the basis of structural differences in capsular polysaccharide, major outer membrane proteins (OMPs), porins and others. A t present 13 serogroups of meningococcus are known viz., A, B, C, E, H, I, K, L, M, X, Y , Z, W135 etc., based on differences in capsular polysaccharides. Meningococci are further subdivided into 20 serotypes based on the different OMP antigens. 1-4 Serogroups A, B C,Y and W135 are responsible for more than 90% of infections. Serogroup A is responsible for sporadic cases and outbreaks in India, Africa and some other developing countries. Serogroups B and C cause infections in the developed world. Serogroup Y has been recently reported in large number of cases of meningococcal disease in the United S tates of America (USA). 3 During 2001-2002 worldwide epidemics caused by serogroup W -135 occurred in association with pilgrimage to Mecca. 3,5 The proportion of cases caused by each serogroup varies by age group, more than half the cases among infants are due to serogroup B in the western world. The epidemics caused by serogroups A and C usually resolve in 1 to 3 years, where as those due to serogroup B begin slowly but may persist for 5 to 10 years. 3,8 The disease is manifested by sudden onset of fever , severe headache, nausea and vomiting, stiff neck and often a petechial rash with pink macules and rarely vesicles. Occasionally the disease may become fulminant with severe sudden prostration, ecchymoses and shock. Meningococcemia may occur with or without meningitis. 1-3 About 10% to 12% of cases result in residual neurological sequelae eg hearing loss, physical disabilities etc. 3,5 Epidemiology , T ransmission, Pathogenesis and Immune Factors The meningococci are a common inhabitant of the human nasopharynx without causing any symptoms or mild local symptoms only . The prevalence of nasopharyngeal carriage of the organism is highly variable (10-20%) and may not correlate with the risk of developing active disease as many of these strains may be non-pathogenic, the carriage may be transient, intermittent or persistent, the strains may be capsulated or non capsulated ones . 2,3 Transmission of the organism occurs from person to person, usually from healthy nasopharyngeal carriers, meningococci are transferred from one person to another either by direct contact or via infectious droplets which can travel for a distance of 1 metre. 3,4 The disease transmission increases during the dry season and declines rapidly after the beginning of the rainy season as the organism cannot survive the moist environment. 4 The transmission rate of virulent clones of bacteria is higher and invasive disease often occurs within first week after acquisition of the organism, whereas some persons may carry pathogenic meningococci for many months or years without getting the disease, various bacterial virulence factors (presence of capsule, pili, endotoxin production) as well as host factors influence the outcome, host defences are determined mainly by humoral responses and to some extent by cellular responses both innate and adaptive in nature.

18 Pneumococcal V accine S.K. Sharma, T . Kadhiravan Lower respiratory infections including community-acquired pneumonia (CAP) are an important cause of morbidity and mortality worldwide. In fact, lower respiratory infections (tuberculosis and chronic obstructive pulmonary disease excluded) are the third most common cause of death in low- and middle-income countries, accounting for about 3.4 million deaths annually . 1 Likewise, lower respiratory infections are the second leading cause of disability- adjusted life years (DAL Ys) lost in low- and middle-income countries. 1 The population level burden of lower respiratory infections among adults in India is not well studied. In the only available published source of data, it was found that 536 of 592 (91%) episodes of CAP were among children. 2 Notwithstanding, data from the industrialized countries suggest that CAP is very common among the elderly (aged > 65 year s). 3 A vast majority of the lower respiratory infections are caused by viral infections. However , most cases of CAP are of bacterial origin. Among the bacterial pathogens causing CAP , S. pneumoniae is the sing l e most common organism, worldwide. 4 In developing and underdeveloped countries, the proportion of CAP caused by S. pneumoniae might be even higher . In a study conducted in Kenya, S. pneumoniae was the most common (46%) identifiable cause of CAP in adults. 5 Overcrowding, outdoor as well as indoor air pollution, and differences in the virulence of prevalent serotypes are considered to confer a higher risk of S. pneumoniae infection among persons living in developing countries. Burden of Pneumococcal Infections Apart from causing CAP , S. pneumoniae infection causes a wide variety of clinical syndromes such as sinusitis, otitis media, tracheobronchitis, empyema thoracis, bacteraemia, meningitis, peritionitis, etc. 6 About one in three to four patients with pneumococcal pneumonia also have bacteraemia. Primary pneumococcal bacteraemia without any apparent primary focus of infection may also occur , especially in splenectomized patients. 6 Pneumococcal pneumonia and invasive pneumococcal disease (IPD) are associated with a substantial risk of mortality . The only available nationally representative data on pneumococcal infections in India come from the Invasive Bacterial Infection Surveillance (IBIS) study conducted by the International Clinical Epidemiology Network (INCLEN) during 1993-97. 7 In this study 7 , pneumococcal pneumonia, bacteraemia, and meningitis were associated with case-fatality rates of 19%, 21%, and 34% respectively . Moreover , about 33% of patients (103 of 314) with proven IPD were younger than 5 years; and about 23% (69 of 304) were older than 50 years. The sensitivity of conventionally employed techniques for the diagnosis of pneumococcal infection, such as culture and demonstration of antigen, is known to be notoriously low , and hence the figures emer ging from the studies are a gross understatement of the true burden of pneumococcal disease. Rather , the proportion of pneumonia cases prevented by vaccination may represent a much better estimate of the true burden of disease (the vaccine probe concept).

Rabies Immunization 19 R.L. Ichhpujani, V eena Mitt al, Shiv Lal, Prasad S. Kulkarni Rabies is an acute viral disease which causes encephalomyelitis in virtually all the warm blooded mammals including man. The causative agent, rabies virus, belongs to the genus L yssavirus and family Rhabdoviridae and is found in wild and domestic animals. Rabies virus is transmitted to other animals and to humans through close contact with their saliva (i.e., bites, scratches, licks on broken skin and mucous membranes). In urban areas, the disease is mainly transmitted by dogs that account for up to 96% of animal bites. Man is the dead end of the infection and does not play any role in its transmission to new hosts. 1 Rabies has frightened humans since antiquity . The fear is by no means unfounded since the disease is invariably fatal and perhaps the most painful of all communicable diseases in which the sick person is tormented at the same time with thirst and fear of water (hydrophobia). Fortunately , the disease is preventable to a large extent if animal bites are managed appropriately and timely In this regard the post exposure treatment of animal bite cases is of prime importance. Burden of the Disease Rabies occurs in all continents with the exception of Australia and Antarctica. However , more than 50 countries in the world have eradicated rabies. Even in infected countries, the disease distribution is not uniform. In many countries, areas free of disease and with a low endemicity are found interspersed with areas with a high endemicity and epizootic outbreaks. In Africa and Asia (with few important exceptions such as Japan and Singapore) rabies is prevalent in almost whole of the territory with a stable pattern. Most of the countries of Americas and Europe report occurrence of disease in limited or border areas. 2 Rabies is responsible for extensive morbidity and mortality in India. The Central Health Education Bureau (CHEB) reported around 6700 deaths due to hydrophobia during 1996. The estimated number of deaths per year is, however , around 19,000. 3 Almost 23 lakh people annually receive post exposure prophylaxis against rabies following bite or exposure to rabid or suspected rabid animal. 4 W ith the exception of Andaman & Nicobar and Lakshadweep islands, human cases of rabies are reported from all over India, with cases occurring throughout the year . 5 About 96% of the mortality and morbidity is associated with dog bites. Cats, wolf, jackal, mongoose and monkeys are other important r eservoirs of rabies in India. Bat rabies has not been conclusively reported from India. Animals implicated in transmitting rabies in India are listed in T able 1.

Rotavirus V accines 20 Pooja Sharma, Nita Bhandari Rotavirus is the most common cause of diarrhoea related morbidity and mortality worldwide. The national estimate of 122,270 rotavirus attributable deaths in under-five-year-old children puts India in the number one spot for deaths due to rotavirus diarrhoea worldwide; 23% of all rotavirus deaths under 5 years of age occur in India. 1 Rotavirus causes one death in about 250 children in the developing world. 2 Diarrhoeal hospitalizations attributable to rotavirus appear to have increased between 2000 and 2004 from nearly 22% to 39%. 3 Several factors may be responsible; improvements in sanitation for one, are likely to have a greater impact on bacterial and parasitic diarrh oeae than viral ones. Difficulty in administration of oral rehydration therapy (OR T ) in children with severe vomiting which is a common occurrence in rotavirus gastroenteritis is another factor . Rotavirus gastroenteritis also does not have a specific treatment unlike for bacterial and parasitic diarrhoeae . Diarrhoeal hospitalizations attributable to rotavirus are similar in countries with different income levels, increasing slightly with increasing income levels suggesting that improvements in water and sanitation will not reduce the incidence of rotavirus infection. 3 Natural history studies suggest that a single infection with rotavirus provides a solid immunity and that it improves with each subsequent infection. 4,5 Therefore, vaccines represent a realistic approach to preventing severe morbidity and mortality due to rotavirus infections. These factors together have made the development and introduction of a rotavirus vaccine the highest priority for the W orld Health Or ganization (WHO) and Global Alliance for V accines and Immunizations (GA VI). Microbiology Rotavirus is a genus of the double stranded ribonucleic acid (RNA) virus of the family Reoviridae. The mature virus particle is a wheel shaped triple layered icosahedron approximately 70 nm in diameter . Rotaviruses are classified into seven different serogroups (A-G) on the basis of antigenic specificity of the capsid proteins in the virus, as well as on the basis of the pattern of the electrophoretic mobility of the 11 RNA segments of the viral genome. The G and P serotypes are defined on the basis of reactivity to specific monoclonal antibodies. All known G serotypes correspond to genotypes. A rotavirus strain is identified by a G genotype, indicated by a number , followed by its P type. At least 15 G genotypes and 25 P genotypes have been identified to date. 6 Of the seven known rotavirus serogroups, only groups A-C are known to infect humans. Group A rotaviruses cause severe, life threatening disease in children worldwide. W ithin group A, four dif ferent subgroups (SG): SGI, SGII, SG I and II and non I/ non II have been distinguished on the basis of VP6 diversity . Group B rotavirus has reported to have caused severe disease in infants and adults in China but not elsewhere. Group C rotavirus causes occasional outbreaks of rotaviral disease in humans. The other groups are limited to animal strains. Rotavirus strains are species specific and do not cause disease in heterologous host.

T yphoid V accines 21 Reeta Rasaily, S.K. Bhattacharya T yphoid fever generally known as enteric fever or bilious fever is caused by the bacterium Salmonella enterica serover typhi , a highly virulent and invasive enteric pathogen. It is a major cause of morbidity in children and adults with an estimated global annual incidence of 22 million cases and 200,000 deaths. 1 T yphoid fever continues to be a major public health problem in many developing countries mostly affecting children in the 5 to 15 years age group; however in endemic areas, children under 5 years of age are also equally affected. 2 Disease Burden T yphoid fever occurs in all parts of the world but is most prevalent in tropical and subtropical countries. The infection is common mainly in South- East Asia (> 100 cases per 1 00,000 population annually), Africa, Latin America and the Caribbean and Oceania. An estimated 90% of global burden of deaths takes place in Asia. W ith improvement of environmental sanitary conditions, the incidence of typhoid fever has declined gradually in developed countries, such as, the United States of America (USA). However , even in developed countries, cases which occur due to infection acquired from travel are frequently encountered. The real impact of typhoid fever is difficult to estimate as the clinical picture is confused with many febrile conditions and lack of bacteriological confirmation in most of the developing countries. However , the social and economic impact of typhoid fever resulting hospitalization of patient with acute disease and its complications and loss of income due to clinical illness is high . 3 A recent prospective multicentre study 4 compared disease burden of typhoid fever across Asia in children 5 to 15 years old. High incidence of typhoid fever (per 100,000 person years) was observed in India (493.5) and Pakistan (412.9), while the incidence in V ietnam, China and Indonesia were 24.2, 29.3 and 180.3 respectively . 4 Overview of the Disease T yphoid fever usually an endemic disease; however , epidemics often occur due to breakdown in water supplies and sanitation. Humans are the only natural host and reservoir . The infection is spread by faecal oral route through ingestion of food or water contaminated with excreta (urine and stool) from typhoid fever cases and asymptomatic carriers. After ingestion, the bacteria reaches the reticulo- endothelial system (intestinal lymph nodes, liver and spleen) via blood and multiply intracellularly within macrophages. The incubation period is 5 to 21 days. The size of inoculum and type of vehicle in which organisms are ingested influences attack rate and incubation period. The patient experiences fatigue, headache, abdominal pain and fever . Older children are often constipated and younger children may have diarrhea. Severe forms of typhoid fever may lead to neuropshychiatric manifestations like delirium and shock, intestinal perforation and haemorrhage. Other symptoms include bradycardia, rose spots, hepatomegaly and splenomegaly . 5,6 The overall case fatality rate is about 4% irrespective of treatment and 1% to 4% of patients become chronic carriers. Immunological protection against typhoid fever results from both humoral and cell mediated immune responses. One attack of typhoid fever usually results in lifelong immunity .

Y ellow Fever V accine 22 Gautam Ahluwalia, S.K. Sharma As of now , no case of yellow fever has been reported from India. However , with the increasing Aedes aegypti mosquito population, the threat looms large over our country . The simian population (reservoir for yellow fever) has also increased manifold over the last few years. Increasing urbanization and diminishing forest cover have resulted in human habitats becoming more vulnerable to contact with the simian species. Presently , the only missing link in the chain is the absence of yellow fever virus. Moreover , many of the clinical features of yellow fever overlap with malaria, dengue, chikungunya and typhoid fever . It is, therefore, imperative that a strict vigil against this disease is maintained in our country by developing a robust surveillance system against yellow fever . 1 Epidemiology Y ellow fever is caused by a single-stranded RNA virus belonging to the family flaviviridae . The same family also includes the virus causing dengue fever . Y ellow fever is an endemic zoonotic disease interspersed with epidemic outbreaks occurring in sub-Saharan Africa and tropical South America. The principal vector for yellow fever is Aedes aegypti mosquito, which is common to dengue virus. In fact, it is rather intriguing that yellow fever has never been reported from India and other Asian countries which are endemic for dengue. A possible reason is that Asian strains of Aedes aegypti are less ef ficient vectors for yellow fever than strains from Africa and Latin America. 2-4 Besides human beings, the principal host for the virus is the non-human primate monkey . However , the true reservoir of yellow fever is the vector Aedes aegypti , which hibernates the virus in its eggs. The eggs are resistant to dry weather and they hatch during rainy season. As a result, the virus is ready for transmission during the next rainy season in the endemic areas. There are basically three cycles of transmission namely sylviatic (jungle), intermediate and urban. The jungle cycle is maintained between monkeys and the virus in the forests. The intermediate cycle occurs in areas where simian and human habitats overlap in the rural setting, whereas the urban cycle occurs when urban mosquitoes are infected by the virus. The human outbreaks are mainly due to the urban cycle where the mosquitoes breed in stagnant domestic water during rainy season. 2-4 Clinical Spectrum of Y ellow Fever The incubation period of yellow fever following an infected mosquito bite varies from three to seven days. The majority of patients present with a viral fever like illness. The patients develop fever , body aches and malaise. In India, the symptoms mimic dengue fever or chikungunya fever . In 10% to 15% cases, the illness is more severe with high fever , chills, nausea, vomiting and severe myalgias. On examination, the patients have pulse fever dissociation as observed in typhoid fever . T h e patients also have conjunctival suffusion and facial flushing. In 50% of these patients, the fever settles down for 24 hours to 48 hours and then recurs. This biphasic illness is associated with abdominal pain, bleeding, jaundice, renal failure and myocardial injury . The hepatorenal involvement has a fatality rate varying from 20% to 50%.

T uber culosis V accine: 23 Immunology , S trategies and S tatus Dipendra K. Mitra, Prabhat K. Sharma Tuberculosis (TB) still remains a major health problem worldwide causing death of 2 million people annually . The developing countries of South-East Asia and sub-Sahara Africa are most severely affected with high prevalence. 1 The probability of developing active disease in an individual s lifetime is about 5% to 10% for most infected individuals, but in the case of co-infection with human immunodeficiency virus (HIV) and TB, it is approximately 10% per year . Malnutrition and other factors leading to immunological deficits (especially HIV infection) are among major reasons for the persistent spread of this ancient disease. 2 Even after the worldwide use of bacille Calmette- Guerin (BCG) vaccine and DOTS, the threat caused by the disease has not waned. 2 The presently available BCG vaccine against TB has been largely ineffective in controlling the disease, particularly among adults. 3,4 In addition to emergence of multidrug-resistant (MDR) strains of the bacillus causing multidrug-resistant-TB (MDR-TB), recently extensively drug-resistant (XDR) strains have posed serious threat to human health. 1,2 It is reported that in addition to pathogen virulence, the host immune response plays a major role in determining the clinical outcome of infection with M. tuberculosis. Following exposure to M. tuberculosis , majority of individuals can contain the primary infection with subsequent latentcy of infection. Reactivation of latent foci due to impairment of host immunity cause active disease in these subjects. 5,6 This indicates that host immunity against the bacilli can contain the disease and thus possibility of facilitating the host immunity , particularly by ef fective boosting of immunological memory with putative vaccine preparations appears to be an attractive approach for controlling tuberculosis. Infection and Disease M. tuberculosis infects human beings via respiratory tract. The precise basis of host immune response against it is yet to be resolved conclusively . The microor ganism is an acid-fast rod shaped bacillus, shielded by a unique cell wall that is composed of long-chain fatty acids, glycolipids and other components which help the bacillus in surviving inside the host phagocytes. These mycobacterial glycolipids are source of potent antigens for T -cells. 7 As,the mycobacterium reaches the lower respiratory tract, it is taken up by the macrophages in the alveoli, where it resides with eventual formation of granuloma, the pathologic hallmark of tuberculosis. Granuloma consists of macrophages, giant cells, T - cells, B-cells and fibroblasts arranged in a systematic manner to form a wall to contain the infection. The failure of immune response directed to contain the infection can result in reactivation and replication of the bacilli, with necrosis and damage to affected lung tissue. 5,8 Infected individuals can control the growth of M. tuberculosis by recruiting large number of activated macrophages and cytolytic T - cells at the site of infection. As the bacilli are harbored in the macrophages, antibody mediated responses are of limited value in host immunity against tuberculosis.

24 V aricella and Herpes Zoster V accines Swati Y . Bhave V aricella, commonly called chicken pox, is caused by varicella zoster virus (VZV) and is characterized by an itchy , vesicular rash, usually starting on the scalp and face, and initially accompanied by fever and malaise. As the rash gradually spreads to the trunk and extremities, the first vesicles dry out hence the vesicles are at various stages (pleomorphic rash) .1 V aricella is usually a benign childhood disease, and rarely rated as an important public health problem but occasionally it can be complicated by VZV -induced pneumonia (especially in adults) or central nervous system (CNS) involvement with encephalitis or acute cerbellar ataxia, thrombocytopenia, glomerulonephritis, arthritis and hepatitis, sometimes resulting in persistent sequelae or death. 1-3 The VZV is a double-stranded deoxyribonucleic acid (DNA) virus of Herpes virus family . Only one serotype is known, and humans are the only reservoir . The V Z V enters the host through the nasopharyngeal mucosa, and almost invariably produces clinical disease in susceptible individuals, secondary attack rate being close to 90% in susceptible household contacts. Once a case has occurred in a susceptible population, it is very hard to prevent an outbreak. It is transmitted by droplets, aerosol, or direct contact. It replicates at the site of entry and the lymph nodes. A primary viraemia follows and skin involvement is seen during the second viraemia. The incubation period is usually 14 to 16 (10-21) days. 2 The incubation period may be prolonged to 28 days if varicell zoster immunoglobulin (VZIG) or intravenous immunoglobulin (IVIG) have been adminstered or may be shortened in an immunocompromised host. Patients usually become contagious from a few days before the onset of rash until the time the rash becomes crusted. Generally , 250 to 500 skin lesions may be evident. It normally takes about 7 to 10 days for all crusts to disappear . 3 Haemorrhagic varicella can be seen in immunocompromised hosts 3 . Disfiguring scars may result from secondary bacterial infections of the vesicles. 4,5 and necrotizing fasciitis or septicemia may also occur . In immunodeficient patients including those with human immunodeficiency virus (HIV) infection, varicella infection tends to be severe and herpes zoster may be recurrent. Severe and fatal varicella infection may also occur occasionally in children taking systemic steroids for treatment of asthma. 2 V aricella in Pr egnancy and in Neonates Foetal and maternal varicella infection in the first and second trimester can result in foetal death and embryopathy resulting in the rare c ongenital varicella syndrome. This syndrome is characterized by limb hyperplasia, cutaneous scarring, eye abnormalities and damage to the CNS. 3,6 Children exposed to VZV in the second 20 weeks can develop inapparent varicella and subsequent herpes zoster early in life without developing extra-uterine varicella. Perinatal V aricella in is seen in newborns when the mother develop chickenpox during the period ranging from 5 days prior to delivery to 48 hours after delivery . If varicella develops in the mother more than 5 days before delivery , the severity of the disease in the newborn is modified by the transplacental transfer of VZV specific maternal immunoglobulin G (IgG) .

For Private Circulation Only ADUL T IMMUNIZA TION (Monograph) V ol. 1, March 2009 Editors: Drs. S.K. Sharma, R.K. Singal, A.K. Agarwal © All Rights Reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher . This book contains views and opinions of a group of experts and does not represent the decisions or stated policies of the Association of Physicians of India or the Editor(s). The publisher disclaims responsibility for opinions expressed by authors and contents of the manuscripts. Published by D r . R.K. Singal Past-President, Association of Physicians of India For the Association of Physicians of India Unit No. 6 & 7, Turf Estate, Opp. Shakti Mills Compound O f f Dr . E.