Update on Available Vaccines in India: Report of the APPA VU 2010: I

Abstract

The Asia Pacific Pediatric Association Vaccinology Update 2010 was held in Mumbai on November 13–14, 2010 to discuss the latest information on burden of infectious diseases, recent developments in vaccines and their impact on immunization practices against infectious diseases occurring in Indian children. During the conference the importance of including conjugate Haemophilus influenzae type b vaccine and anti-rabies vaccines in routine immunization was stressed. Also, the need for giving a second dose of measles mumps rubella vaccine at school entry; and the need for a two-dose varicella vaccine regimen (first dose at 12–15 months of age and a second dose at age 4–6 years) was elucidated. Information related to vaccines which have become available in India in recent years, namely, inactivated poliovirus vaccine; diphtheria, tetanus, acellular pertussis (DTaP) vaccine; conjugate pneumococcal vaccine; rotavirus vaccines; H1N1 vaccines; live attenuated hepatitis A virus vaccine; oral cholera vaccine; tetanus, reduced-dose diphtheria, acellular pertussis (Tdap) vaccine; and human papillomavirus vaccines were discussed.

Introduction

The Asia Pacific Pediatric Association Vaccinology Update 2010 (APPA VU 2010) was held in Mumbai on November 13–14, 2010. The conference was hosted by the Mumbai and Navi Mumbai branches of the Indian Academy of Pediatrics to discuss the latest information on burden of infectious diseases, the latest developments in vaccines and their impact on practices and policies related to immunization against infectious diseases occurring in children. This first part of the conference report discusses the interesting information about vaccines which are already available in India for many years; and vaccines which have become available in recent years.

Hib Vaccine: How Important is it for Indian children?

The acute need to include the conjugate Haemophilus influenzae type b (Hib) vaccine in the Universal Immunization Program (UIP) by the Government of India was stressed. Of the estimated 8.8 million deaths in children younger than 5 years worldwide in 2008, infectious diseases caused 68% (6.0 million), with the largest percentages due to pneumonia (18%, 1.6 million) [1]. Of these, 49% (4.3 million) of child deaths occurred in five countries: India, Nigeria, Democratic Republic of the Congo, Pakistan, and China [1]. Conjugate Haemophilus influenzae type b (Hib) vaccines have almost completely eliminated Hib disease (severe pneumonia and meningitis) in both developed (US, Europe) and developing countries (such as Kenya, The Gambia, Uganda) in which they are routinely used [2]. These vaccines also reduce asymptomatic nasopharyngeal carriage and substantially protect unvaccinated children through improved herd immunity even at moderate vaccine coverage of 40%–50% [2]. However, Hib vaccine has not yet been introduced in the UIP because of high cost, concerns about program sustainability, limited vaccine supply, and uncertainty about Hib disease burden. In 2006, the World Health Organization (WHO) has urged all countries to move forward with Hib vaccine introduction at the national level [3].

A recent multi-center surveillance study from India (Chandigarh, Kolkata, Vellore) has reported that there is a significant burden of Hib disease among children in India [4]. In Vellore, currently 35%–60% of children below 2 years of age receive three doses of Hib vaccine through private purchase. This has resulted in a significant reduction in Hib meningitis admitted to its referral hospital over time (2001–2005). The annual mean number of Hib meningitis cases fell to 3.8 from 10.7 before Hib vaccine introduction (P < 0.0001) [5]. The National Technical Advisory Group on Immunization (NTAGI) in India has strongly recommended that Hib vaccine should immediately be introduced in India’s UIP [6].

Need for Routine Pre-exposure Prophylaxis of Rabies

Rabies is a fatal illness and it is endemic in India. Annually, about 20,000 human rabies deaths (of these 40% are in children below 15 years of age) and 17 million animal bites are estimated to occur in our country [7, 8]. To make matters worse, in India in almost 40% of bite victims the mandatory thorough washing of bite wounds and scratches with soap and water is not done properly and the use of rabies immunoglobulin in patients presenting with Category III exposures is abysmally low (2.1%) [9]. India has approximately 25 million dogs, with an estimated dog: man ratio of 1:36 [9]. There is a large population of stray dogs (about 15–20 million); and only 33% of pet dogs are properly vaccinated against rabies [9].

Historically, due to their high reactogenicity, nerve tissue vaccines (e.g., Semple vaccine) were only recommended for post-exposure prophylaxis (PEP). Since December 2004, the Semple vaccine is no longer manufactured and it has been replaced by safe and effective modern tissue culture vaccines which are recommended for both pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) vaccination regimens [10]. In 2005, the WHO has specifically recommended administration of PreP for school-aged children living in highly endemic areas where canine rabies is not well controlled [10]. Children playing outdoors are particularly vulnerable to dog bites since unvaccinated stray dogs are commonly observed on the streets and on or around public and school playgrounds. Furthermore, children may not report animal bites to their parents or may delay reporting of bites [10].

The WHO pre-qualified vaccines such as the purified chick embryo cell vaccine (PCECV) or the purified verocell rabies vaccine (PVRV) are safe and immunogenic when administered intramuscularly for pre-exposure prophylaxis of rabies in children [11]. They are administered as a three-dose intramuscular (given on deltoid muscle) pre-exposure regimen on days 0, 7 and 28 [10, 11]. According to the current WHO recommendations, in case of an exposure to rabies only two additional doses of rabies vaccine are necessary (on days 0 and 3 post-exposure) for protection of those who have previously received a complete pre-exposure immunization course, and, most importantly, in such patients no rabies immunoglobulin administration is required for Category III wounds [10, 12].

MMR Vaccine: Justifying the Second Shot

Measles continues to be an important cause of childhood morbidity and mortality in many states in India and between 100,000 and 160,000 children die from measles in India each year [13]. The WHO has recommended that in countries with ongoing transmission, in which the risk of measles mortality among infants remains high (as in India), the first dose of measles vaccine should be administered at age 9 months [14]. However the average seroconversion rate with measles vaccination at 9 months is only 85% (range 70%–98%) [13]. As the level of ‘herd immunity’ needed to significantly impact measles transmission is in the range of 93%–95%, even 100% coverage with a single dose of measles vaccine administered at 9 months of age will not prevent the accumulation of a susceptible pool and consequent periodic measles outbreaks [13]. A recent (2006) vaccination coverage survey in India showed overall 71% coverage for measles vaccine (given during 9–12 months of age) [13].

For these reasons, the WHO has recommended that countries wherein measles vaccination is delivered at age 9 months, should also administer a second dose of measles vaccine at age 15–18 months [14]. Giving the Measles, Mumps, Rubella (MMR) vaccine at 15–18 months serves this aim.

Children and adolescents who had two doses of the MMR vaccine are better protected against measles, mumps and rubella compared with those who had only one dose of the vaccine [15–18]. The minimum interval between the first and second MMR doses is 1 month [18]. For logistic reasons, the second dose at school entry (4–6 years of age) was recommended.

Monovalent Rubella Vaccine for Adolescent Girls

In India, rubella remains endemic as MMR vaccine is not part of the universal immunization program. Also, there is no reliable surveillance system for congenital rubella syndrome (CRS). The estimated incidence of CRS ranges from 32 to 97 per 100,000 live births in India [19].

The level of ‘herd immunity’ needed to significantly impact rubella transmission is around 80% [19]. Implementation of a universal two-dose MMR vaccine policy will thus help achieve control rubella transmission and eventually eliminate rubella and CRS [19]. But this strategy carries the risk of increasing the average age of rubella cases thus resulting in increased, instead of reduced, numbers of CRS cases if vaccination coverage is insufficient [20]. Prevention of CRS can only be achieved by immunization of adolescent girls and/or women of childbearing age [20]. Therefore, there is an acute need to implement mass scale one-time immunization with monovalent rubella vaccine for adolescent girls in our country [21].

Varicella Vaccine: One Dose or Two Doses?

The implementation of a universal one-dose childhood varicella vaccination program in the United States in 1995 resulted in a dramatic decline in varicella morbidity and mortality [22]. However, outbreaks of varicella continued to be reported increasingly in highly vaccinated school children [22]. The initial varicella vaccine policy recommendations were for one dose of varicella vaccine for children aged 12 months to 12 years and two doses, 4–8 wks apart, for persons aged >13 years [22].

One-dose varicella vaccine is 85% effective in preventing varicella and >95% effective in preventing severe varicella disease (>100 skin lesions) [22]. But breakthrough varicella disease (that develops >42 days after vaccination) still would occur in 15% of children. This breakthrough varicella typically is mild, with <50 skin lesions, low or no fever, and shorter (4–6 days) duration of illness. The rash is more likely to be predominantly maculopapular rather than vesicular. Nevertheless, breakthrough varicella is contagious [22].

Data from a randomized clinical trial conducted post-licensure over 10 years has indicated that vaccine efficacy after two doses of varicella vaccine in children is 98.3% (95% CI, 97.3–99.0) and significantly higher than that after a single dose (94.4%, 95% CI, 92.9–95.7). The risk for breakthrough disease was 3.3-fold lower among children who received two doses than it was among children who received one dose [23].

In order to provide improved protection against disease and further reduce morbidity and mortality from varicella in June 2006, Advisory Committee on Immunization Practices (ACIP) approved a routine 2-dose recommendation for children in US [24]. The first dose is now to be administered at age 12–15 months and the second dose at age 4–6 years [24]. A second dose of varicella vaccine, now recommended for all children, could improve protection from both primary vaccine failure and waning vaccine-induced immunity [25, 26]. During the conference, two doses of varicella vaccine with a similar schedule was recommended for children in our country whose parents chose to give the vaccine after a one-to-one discussion with their pediatrician.

OPV and Risk of VAPP

Mass vaccination with live attenuated trivalent oral poliovirus vaccine (tOPV) in the form of routine universal immunization program (UIP) and annual two-monthly pulse polio immunization programs has led to a drastic reduction in the number of poliomyelitis cases in India [27]. Wild poliovirus type 2 (WPV2) has been eradicated since 1999 [27]. By the year 2006, barring the two large adjoining states in northern India, namely, Uttar Pradesh and Bihar, indigenous transmission of wild poliovirus virus (WPV1 and WPV3) has been eliminated in India [27].

Monovalent oral polio vaccine (mOPV) has a higher efficacy against WPV than tOPV in supplementary immunization activities (SIAs) [28]. In 2006, preferential use of mOPV1 in the form of SIAs was implemented and WPV1 cases decreased from 83 in 2007 to 18 upto May 2009 [27]. However there was a simultaneous resurgence of WPV3 cases in Uttar Pradesh and an outbreak in Bihar. Hence, additional SIAs using mOPV3 were implemented in 2007, and the number of WPV3 cases declined from 794 in 2007 to 41 upto May 2009 [27]. In 2010 bivalent oral poliovirus vaccine types 1 and 3 (bOPV1,3) have been implemented in SIAs to eradicate poliomyelitis in Uttar Pradesh and Bihar with great success [29, 30]. Till September 2010, only 32 cases of poliomyelitis have occurred compared with 260 in 2009 [30]. Till India achieves consecutive 3-years polio-free status, mass use of OPV in routine UIP and annual pulse polio programs will continue [31, 32]. Only after India becomes polio-free an official policy decision on including the inactivated poliovirus vaccine (IPV) in the UIP and gradual phasing out of OPV is expected to be taken [31, 32].

It is well known that the live attenuated strains in the OPV replicate in the human gut and are excreted for several wks after immunization [31]. During this period, the attenuating mutations in the vaccine strains can rapidly revert. This may, in rare cases (1 per 4.5 million OPV doses) cause vaccine-associated paralytic poliomyelitis (VAPP) in vaccinees [31]. Clinically, VAPP is indistinguishable from polio caused by wild poliovirus, with an identical incubation period, range of severity and case-fatality rate [31]. Data on the incidence of VAPP is not in the public domain; and VAPP are considered as non-polio cases and not reported [31]. But considering the current usage of millions of OPV doses in Indian children, it can be speculated that at least 180–200 children would be getting VAPP every year. Thus at present, incidence of children suffering from VAPP in India is most probably higher than wild poliovirus paralytic cases.

In May 2006, inactivated poliovirus vaccine (IPV) was licensed in India [32]. IPV is a safe and effective (but expensive) vaccine. VAPP cannot arise from the inactivated poliovirus vaccine (IPV) [33]. IPV is currently used only in the private sector and only affording parents are able to protect their children against VAPP. IPV is given along with OPV at 6, 10, 14 wks and a booster at 15–18 months of age [34]. These affording children are also strongly advised to continue participating in the national pulse polio immunization drives [34].

DTwP Versus DTaP: Which to Recommend?

Children in India and in the developing world are still being immunized with the Diphtheria, Tetanus, whole-cell Pertussis (DTwP) vaccine. It is well known that the DTwP vaccine often causes minor (but troublesome) side effects such as mild-moderate fever, erythema, swelling, fretfulness, drowsiness and rarely, more serious adverse effects such as high fever >40°C, seizures and hypotonic-hyporesponsive episodes. Over the last decade in many developed countries the much more expensive Diphtheria, Tetanus, acellular Pertussis (DTaP) vaccine has replaced the DTwP vaccine as it has an improved reactogenicity profile, especially for the minor side-effects [35–39]. Both the DTwP and DTaP vaccines are highly effective (75%–90%) in reducing pertussis-related morbidity and mortality [40, 41].

Recent studies have shown that although acellular pertussis vaccines are well tolerated, whole-cell pertussis vaccines better enhance immune responses to co-administered Hib vaccine [42]. Combination of DTaP with conjugated Hib vaccine results in statistically significant reduction in antibodies to Hib antigen [42]. However, most European countries do not regard this as clinically significant as the slightly lower immunogenicity is unlikely to be clinically relevant in the few months after primary Hib immunization. Also, the booster dose of Hib in the second year of life would sustain population immunity against Hib infection through childhood and maintain low rates of invasive disease [42].

Pneumococcal Conjugate Vaccine

Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and sepsis in children worldwide, including India [43]. The estimated pneumococcal deaths in Indian children aged 1–59 months per 100 000 is between 100 and <300 [43]. However, there is no detailed knowledge of pneumococcal serotypes causing invasive disease in Indian children [44].

It is well known that infants and young children <2 years of age are at great risk of invasive pneumococcal disease. In the USA and several Europe countries, 7-valent pneumococcal conjugate vaccine (PCV-7) has been introduced in the routine immunization schedule with great success in preventing invasive pneumococcal disease [45, 46]. The PCV-7 has been designed to protect children in developed countries; and hence serotype coverage is 90% for USA and 75% for Europe [45, 46]. It is estimated that the serotype coverage for India is 53% or lower [47, 48]. The WHO expert committee has recommended that a pneumococcal conjugate vaccine should be covering at least 70% serotypes prevalent in the country in which it is being introduced [49]. Hence, the PCV-7 vaccine does not guarantee Indian infants protection from invasive pneumococcal disease, but can only reduce the risk. Also, it is an expensive vaccine (three doses at 6, 10, 14 wks and one booster at 15–18 months) and may be considered if parents demand it after one to one discussion.

Recent surveillance reports from USA have confirmed that routine immunization with the PCV-7 vaccine has over the years led to replacement with non-PCV 7 serotypes in the community [50, 51]. There is a potential risk of invasive pneumococcal disease occurring due to these non-PCV 7 serotypes some of which may be resistant to routinely used antibiotics [50, 51]. This concern has now led to including these non-PCV 7 serotypes in the recently manufactured pneumococcal conjugate vaccines, namely, the 11-valent pneumococcal conjugate vaccine (PCV-11) and the 13-valent pneumococcal conjugate vaccine (PCV-13) [52].

Rotavirus Vaccines

Rotavirus infection is the leading cause of severe acute diarrhea among young children worldwide [53]. An estimated 527,000 children aged <5 years die from rotavirus diarrhea each year, with >85% of these deaths occurring in low-income countries of Africa and Asia [53]. Annually in India, rotavirus diarrhea causes an estimated 122,000–153,000 deaths, 457,000–884,000 hospitalizations, and 2 million outpatient visits in children <5 years of age [54]. The Indian Rotavirus Strain Surveillance Network carried out a multi-centric study in seven different regions of India and reported that rotavirus was detected in stools of 39% children aged <5 years (of 4243 enrolled) who presented with acute gastroenteritis and required hospitalization with rehydration therapy for at least 6 h [55].

Rotavirus vaccines have shown efficacy of 85%–98% against severe rotavirus diarrhea in trials conducted in America and Europe [53, 56, 57]. Compared to data from developed countries, vaccine efficacy against severe rotavirus diarrhea is lower in African countries (Ghana, Kenya, Mali: 39·3%, 95% CI, 19·1–54·7) and in Asian countries (Bangladesh, Vietnam: 48·3%, 95% CI, 22·3–66·1) [58]. However, the increased prevalence of severe disease in these African and Asian countries means that these vaccines could still substantially reduce rotavirus mortality and morbidity [58]. Consequently, in December 2009, the WHO has made rotavirus vaccine introduction in developing countries a high priority [59].

In 2006 two new live, oral, attenuated rotavirus vaccines were licensed in US and Europe: the pentavalent bovine-human reassortant vaccine and the monovalent human rotavirus vaccine [60]. Since then they have been introduced into routine immunization programs in 11 countries in these regions and in Australia and recently in four Latin American countries (Brazil, Panama, Venezuela, and El Salvador) [58, 60]. The monovalent human rotavirus vaccine has been marketed in India and has been reported to be immunogenic, safe and well-tolerated in healthy Indian infants [61].

The monovalent human rotavirus vaccine is given in two doses; the first oral dose administered at 6–15 wks of age, with an interval of 4–8 wks prior to second dose; and the vaccination course should be completed by the age of 24 wks [56, 60]. In USA, the upper age limit for the second dose has recently been recommended to be 32 wks of age by the Advisory Committee on Immunization Practices [62]. The pentavalent human-bovine reassortant rotavirus vaccine is given similarly but in three doses; the first oral dose administered at 6–15 wks of age, and the third dose no later than 32 wks of age [60].

H1N1 Vaccines

In early April 2009, a new influenza A (H1N1) virus (‘swine-origin influenza virus’) emerged among humans in Mexico, quickly spreading worldwide through human-to-human transmission [63]. On June 11, 2009, the WHO raised the pandemic alert to level 6, in view of the number of countries and regions which officially reported influenza A (H1N1) virus cases. A characteristic feature of the H1N1 virus is that it disproportionately affected infants, children and young adults as well as those with an underlying lung or cardiac disease condition [63].

Although 200 million cases of H1N1 cases have been estimated to have occurred world-wide since the onset of the pandemic, the actual number of remains unknown as most cases were diagnosed clinically (and empirically treated with oseltamivir) and were not laboratory-confirmed [63]. Despite the fairly mild course in most infected individuals, more than 18,449 people died [64]. The H1N1 pandemic affected India too, especially Pune and Panchgani in western India [65, 66]. Since August 2010 the world has entered a “post-pandemic period” and it seems that influenza A H1N1 has “largely run its course” [64]. While in 2009–10 the H1N1 virus caused a mild disease in most infected individuals, the time frame and severity of the next wave remains unknown [64].

The need for a specific vaccine was recognized in 2009 and the WHO promptly initiated vaccine development in collaboration with Health Ministers and National Health Agencies, and the vaccine industry [63]. Two types of vaccines are now available in India: (i) an inactivated injectable H1N1 given intra-muscularly or sub-cutaneously for children 6 months of age and above. Two doses are recommended 4 wks apart; (ii) a single-dose indigenously-developed intra-nasal vaccine, for children 3 years and above. This single-dose vaccine is to be sniffed once in each nostril and is economically priced. Both types of vaccines have been found to be immunogenic, safe and well-tolerated in clinical trials [67, 68].

Emerging Need for Hepatitis A Virus Vaccine

Because of the improvement in living standards, the pattern of Hepatitis A virus (HAV) in India is changing from asymptomatic/mild childhood infection to an increased incidence of symptomatic/severe disease [69–71]. Also, it has been observed that 15% of children with acute hepatitis A infection have atypical presentations, such as prolonged cholestasis, acute liver failure, relapse, ascites, and bleeding manifestations which are associated with increase in morbidity [72]. There is a definite need for formulating vaccination strategies for HAV in Indian children, especially those from the higher and middle strata of society who no longer are getting exposed to HAV due to improved sanitation and availability of safe drinking water [69–71].

For children, the first dose of any HAV vaccine should be given at 12–23 months of age [73]. Two doses of the inactivated HAV virus vaccine, either the aluminum-adjuvanted vaccine or the aluminum-free, virosome-formulated vaccine, are needed for lasting protection. These doses should be given at least 6 months apart [73]. Both types of inactivated HAV vaccines are equally safe and effective. But the aluminum-free, virosome-formulated HAV vaccine has improved reactogenicity [74]. Inactivated HAV vaccines are expensive and this precludes their widespread use in ‘routine’ schedules in India. Recently, a live attenuated HAV vaccine which is cheaper, equally safe and effective and which requires only a single dose administered subcutaneously in a child above 1 year of age to elicit long-term immunogenicity has become available in our country [75–77].

New Affordable Oral Cholera Vaccine

Cholera notification in India is highly deficient [78]. Of India’s 35 states and union territories, 21 have reported cholera cases during at least 1 year between 1997 and 2006. The states of Orissa, West Bengal, Andaman and Nicobar Islands, Assam and Chhattisgarh accounted for 91% of all outbreak-related cases [78]. In cholera-endemic areas, children younger than 5 years are most affected [78].

Older generation, injectable cholera vaccines were rejected as public health tools in the late 1970’s because of their unacceptable side-effects and limited efficacy [79, 80]. Since 2001, the WHO has recommended a recombinant B-subunit killed whole-cell (rBS-WC) vaccine for use in individuals aged 2 years and older and at risk in endemic regions [79, 80]. The rBS-WC vaccine has demonstrated a 78%–90% protection after two doses in the first 6 months, gradually decreasing to 50% after 3 years [79]. However, the rBS-WC vaccine is not licensed in India and is too costly for routine use in public health settings. In addition, it needs to be ingested with a buffer solution [80].

Recently, a new killed bivalent (O1 and O139) whole cell oral cholera vaccine which is safe and provided protection against clinically significant disease in a cholera-endemic area in Kolkata in individuals aged ≥1 year has become available [81]. The bivalent vaccine has a protective efficacy of 67% up to 2 years [81]. This Indian vaccine has two main advantages over the rBS-WC vaccine, namely ease of administration (no requirement for co-administration of buffer) and its lower cost which makes mass immunization campaigns more feasible [82].

Tdap Vaccine: How Important is it for Older Indian Children?

The incidence of pertussis in adolescents and in adults has been increasing in a number of developed countries (United States, Canada, Italy, Australia, Switzerland and the Netherlands) in recent years [83, 84]. Prolonged cough is often the only clinical feature in these adolescents and adults and their condition is often misdiagnosed because clinicians continue to perceive pertussis as a childhood disease [83, 84]. A number of hypotheses have been put forward to explain the observed disease resurgence, including waning natural and vaccine-induced immunity and a lack of natural boosting [83, 84]. This is of concern because these adolescents and adults have been identified as a source of transmission of pertussis to very young infants who are unimmunized or partially immunized and thus more vulnerable to disease-related complications and higher mortality [83, 84].

In response, several countries (United States, Australia, Canada, Switzerland) in 2006 introduced universal single-dose booster tetanus, reduced-dose diphtheria, and acellular pertussis vaccine (Tdap) immunization to all adolescents between 10 and 18 years of age and all adults up to 64 years of age to reduce outbreaks of pertussis and this has proved to be effective in protecting against pertussis during outbreaks [85, 86].

The option of offering Tdap vaccine instead of tetanus toxoid (TT) vaccine at the age of 10 years to all adolescents in our country who can afford to use the vaccine was stressed during the presentation. It was also mentioned that a recent Indian study has documented that the Tdap vaccine is safe and well-tolerated in Indian children aged 4–6 years, who have previously completed primary vaccination and a booster dose at 16–20 months of age with DTwP vaccine [87]. However,this study had not assessed the immunogenicity of Tdap in this pre-school study population.

HPV Vaccines

Cervical cancer is a leading cause of cancer death among women in low-income countries, with ~25% of cases worldwide occurring in India [88]. In India about 73,000 women die of the disease annually [88, 89]. Persistent infection with high risk types of human papillomavirus (HPV) is established as the key causal agent for cervical cancer [88, 89]. Worldwide, 70% of cervical cancer cases are due to HPV type 16 and 18 (type 16 accounting for 54% and type 18 accounts for about 17% cases), and type 45, 31, 33 and 52 accounting for most of the remaining cases [88, 89]. Non-oncogenic HPV serotypes 6 and 11 are responsible for more than 90% of ano-genital warts [88, 89]. The lag period between infection with oncogenic HPV and invasive cervical cancer is 15–20 years [88, 89]. In India, the most common (80%) oncogenic types are HPV types 16 and 18; with HPV 16 predominating (80%–90%) [90, 91].

Two recently developed virus-like particle based prophylactic HPV vaccines: a quadrivalent (HPV 16/18/6/11) and a bivalent (HPV 16/18) offer great promise to prevent cervical cancer [92, 93]. Both these vaccines translate to protection of cervical cancer in the order of 70%–75%, which represents the percentage of invasive cancers attributable to HPV-16 and 18 [92, 93]. The vaccine is most effective if administered in pre-adolescence girls (age 11–12 years) prior to sexual activity. The vaccine is administered in three doses at 0, 2, and 6 month intervals [92, 93]. However, they are extremely expensive and at present can only be used individually for affording adolescent girls. Clinical efficacy trials for both vaccines demonstrate that protection lasts for at least 5 years [92, 93]. A need for booster doses has not been established [92, 93].