Towards adult vaccination in India: A narrative literature review.

ABSTRACT Despite vast improvements in childhood vaccination coverage in India, adult vaccination coverage is negligible. Our aim was, therefore, to create awareness about the importance of adult immunization. Although the true burden of vaccine-preventable diseases (VPDs) among Indian adults is unknown, adults are particularly vulnerable during outbreaks, due to a lack of immunization, waning immunity, age-related factors (e.g. chronic conditions and immunosenescence), and epidemiological shift. There are no national adult immunization guidelines in India, and although several medical societies have published adult immunization guidelines, these vary, making it unclear who should receive which vaccines (based on age, underlying conditions, etc.). Other barriers to adult immunization include vaccine hesitancy, missed opportunities, and cost. Steps to improve adult vaccination could include: adoption of national guidelines, education of healthcare providers and the public, and promotion of life-course immunization. Improving adult vaccine coverage could help reduce the burden of VPDs, particularly among older adults.


Introduction
India is the second most populous country in the world, with nearly 1.4 billion people, accounting for approximately 18% of the world population. 1 It has been estimated that up to 63 million people in India are pushed into poverty by health expenses each year. 2 Further, while 15% of households faced significant health costs in [2004][2005], this rose to 18% in 2011-2012. 3,4 Although the burden of communicable, maternal, neonatal, and nutritional (CMNN) diseases is declining in India, they still accounted for approximately one third of disability adjusted life years and around one quarter of deaths in 2016. 5 Even though the burden of CMNN diseases was considerably higher among children than adults, among those aged ≥15 years (representing approximately 72% of India's population in 2017 6 ), CMNN diseases still accounted for 14-30% of disability adjusted life years and 17-29% of deaths (depending on age group). 5,7 The discovery of antibiotics in the early twentieth century and the eradication of smallpox in 1979 via vaccination were major breakthroughs in the fight against infectious diseases. 8 However, despite the huge beneficial impact of antibiotics, antibiotic resistance has become one of the greatest threats to global health. 9 Further, the risk of infection has increased greatly with mutation, globalization, and increased travel. 8,10 Therefore, infectious diseases continue to be a major worldwide public health problem 8,11 and vaccine-preventable diseases (VPDs) affect many thousands of adults worldwide, resulting in high morbidity, mortality, and economic burden. 12 Furthermore, unvaccinated adults can spread diseases to infants who have not yet been immunized (e.g. pertussis). 13,14 Therefore, improving adult vaccination coverage could have positive consequences for individuals, families, and communities. Adult vaccination could also help to reduce healthcare costs, 12 which is particularly important among poorer communities.
Various commentaries have highlighted the lack of adult immunization in India 15 and the importance of improving coverage. 10,15,16 In this focused narrative review, we combine and expand upon the information contained in these commentaries in order to create awareness about the importance of adult immunization as an integral component of "life-course immunization". To achieve this, we sought to: (1) highlight the burden of VPDsoverall and among adultsin India; (2) summarize the various Indian adult vaccination recommendations; (3) discuss the reasons for adult VPDs (e.g. lack of adult immunization, waning immunity, immunosenescence, and epidemiological shift); and (4) propose solutions or steps to be taken for the implementation of adult immunization in view of various barriers and challenges (e.g. lack of a coordinated immunization program, lack of knowledge, and vaccine hesitancy). Figure 1 elaborates on the clinical relevance of our findings in a form that could be shared with individuals by healthcare professionals.

Overall burden of VPDs in India
The World Health Organization (WHO) has published the number of reported cases of selected VPDs in India and other countries. 17 While these are acknowledged to "represent only a fraction of cases", they show some interesting trends, both over time and compared to other countries. As shown in Table 1

Burden of VPDs among adults in India
There is a paucity of data on the incidence of VPDs among adults in India. However, some data on human papillomavirus (HPV) infection and cervical cancer are available. For example, random HPV testing of 890 women from India in 2009-2012 found that 12% were HPV positive and 4% were borderline positive. 21 It has been estimated that nearly 97,000 women in India are diagnosed with cervical cancer and over 60,000 die from this disease each year, making it the second most common cancer and the second leading cause of cancer death in India. 22 Further, data from the US Centers for Disease Control and Prevention (CDC) have indicated that, in countries with a last diphtheria booster before age 6 years, approximately half of all diphtheria cases are among those aged ≥15 years, and this was dominated by cases from India. 23 There are also numerous reports of VPD outbreaks in India that have affected predominantly adults, some examples of which are listed in Table 2. [24][25][26][27][28][29][30][31][32][33][34][35]

Adult vaccination recommendations in India
The only nationally recommended vaccine for adults is tetanus toxoid (TT) during pregnancyfor the protection of newborns against tetanus; TT is also recommended at age 16 years. 36 However, it should be noted that this is in the process of being replaced by tetanus and diphtheria toxoid (Td). 37,38,39 Various Indian societies and associations have published vaccination guidelines for all adults, [40][41][42] and for women 43,44 specifically (Table 3). Although these guidelines have some similarities, there are also differences between them. Vaccination advice also depends on various, complex risk factors (e.g. chronic conditions, age, occupations, lifestyle) and vaccination/disease history. Given these discrepancies between the guidelines, it is not clear which vaccines healthy and at-risk adults should receive.

Lack of adult vaccination
Coverage Adult vaccination coverage in India is generally believed to be poor, 15 but we were unable to find reliable estimates of adult immunization coverage in India in the literature. However,   some data on HPV vaccination are available. For example, in a 2014 study of 155 female healthcare professionals in Bangalore, the majority of whom had good knowledge ofand favorable attitudes towardvaccination and screening, none had received HPV vaccination. 46 Barriers to adult vaccination Various reported barriers to adult vaccinationmainly from the USare shown in the red sections of Figure 2. 12,[47][48][49][50] While these barriers are likely also applicable to India, there are probably a number of additional barriers relating to socio-economic factors and religious/cultural beliefs, particularly in rural India. Disease surveillance amongst Indian adults is poor, resulting in under-recognition of outbreaks and a paucity of data on the real burden of VPDs in India. 51,52 In India, there are various adult vaccination recommendations (Table 3), but none has been nationally adopted and no systematic programs are in place to recommend, promote, or fund any of these schedules. The lack of a national commitment to improve adult vaccination has resulted in adult immunization being neglected and underpublicized. Further, over 2/3 of Indian adults are not aware of adult vaccination, many thinking that vaccines are only for children. 53 There is also a lack of infrastructure for adult immunization in India. Even in countries where adult vaccines are nationally recommended, uptake remains suboptimal. 54 In the US, various age-specific vaccinations are recommended for adults. 55 However, survey data from 2015 indicate that uptake in the US only ranged from 23% (for tetanus+pertussis; previous 10 years) to 64% (for pneumococcal disease; ever; among those aged ≥65 years). 56 This is likely due to several factors, including "vaccine hesitancy", which can be caused by complacency (lack of perceived need), convenience (lack of accessibility or affordability), and confidence (lack of trust) (the "3Cs" model). 57 Recently, an additional "C"cultural acceptancehas resulted in the "4Cs" model, because sociocultural, religious, psychological, and political factors can also affect vaccine uptake. 47,58,59 Yearly seasonal influenza vaccination is recommended in India in various guidelines. [41][42][43] Guidelines also recommend influenza vaccination during pregnancy; and it is recommended by the Indian Society of Nephrology 40 for high-risk people, including healthcare workers (Table 3). However, in a 2012-2013 study in Srinagar, 0/1,000 pregnant women and 9/90 obstetricians had received influenza vaccination, mainly due to poor knowledge about their availability and concerns about efficacy. 60 In an Indian interview study, 61 95% of respondents thought that an H1N1 influenza vaccine would be effective, but only 25% were previously aware of pandemic influenza vaccines and only 8% received one during the 2009-2010 pandemic. Barriers to vaccination included a low perceived risk, access and cost issues, insufficient information, and the perceived lack of a government mandate. 61 Similarly, only 13% of 802 students reported receiving influenza H1N1 vaccination during the post-pandemic phase. 62 Most (74%) said that they would definitely/probably not get vaccinated in the future, because of low perceived risk (42%) and a lack of trust in vaccine efficacy (24%) and safety (21%).
Although HPV vaccination is recommended for girls aged 9-18 years 63 and for adults up to various ages (Table 3), [40][41][42][43][44] in a survey of 210 Indian physicians, only 47% knew that HPV vaccines were approved for use in India and only 30% said they would recommend HPV vaccination. 64 In a 2014 study of medical/paramedical students in a teaching hospital in India, only 7% had received HPV vaccination, and 49% of the unvaccinated students said that they would be unwilling to be vaccinated due to concerns about efficacy (30%), safety (26%), cost (22%), and low perceived risk (15%). 65 The cost of vaccinationincluding purchase, distribution, storage, and administration costscan affect uptake. While childhood vaccinations included in India's Univeral Immunization Program are free of cost, 36 the cost of adult vaccinations (apart from TT/Td during pregnancy) is currently borne by the individual.

Waning immunity
It is well recognized that the immunity elicited by vaccines can wane over time, and that this effect is much more pronounced with vaccines against diseases caused by pathogens that have complex life cycles or antigenic variation (e.g. influenza, pertussis). 66 This decrease in immunity years after receipt of childhood vaccines can result in outbreaks or epidemics 66 (Table 2).

Age-related factors
Immunosenescence is a natural, progressive dysregulation and dysfunction of the innate and adaptive immune responses 47,67 (see orange line in Figure 3). This is particularly relevant for older adults, and highlights the importance of vaccination in this age group. 47 However, immunosenescence can alter the efficacy of some vaccines, 67 so older adults may need different vaccines to younger adults. 47 Various age-related conditions (e.g. obesity, chronic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease) can increase the risk of VPDs and/or their complications (e.g. influenza, pneumococcal disease, and hepatitis B). 55,68,69 Worldwide, there is an aging population, with various associated healthcare needs and challenges. [70][71][72] The population in India is also aging, with the proportion of people aged ≥15 years increasing from 68% in 2007 to 72% in 2017; and the proportion of adults aged ≥65 years increasing from 5% to 6%. 6 As the overall population ages, the burden of VPDs will likely increase.
It should also be noted that childhood immunization was only introduced in India in 1978, 73 so anyone aged >41 years in 2019 would likely not have received any childhood vaccination. Further, vaccine coverage remained below 65% until 2014, 74 so many Indian adults aged <41 years would also likely not have received childhood vaccinations. Adult vaccinations are even more important among these unimmunized adults.

Epidemiological shift
Various VPDs that are normally contracted during infancy or childhood are now affecting older children and adults. This epidemiological shift could be due to increasing vaccine coverage among children. For example, in 2013-2014, there was a measles outbreak that affected 20 university students in Karnataka. 29 Similarly, an epidemiological shift in age at diagnosis has also been reported for mumps and rubella to adolescents and adults. 75 This is particularly important during pregnancy, as rubella infection at this time can result in congenital rubella syndrome, which is characterized by congenital organ malformations. 76 Another example is a shift in the age of acquisition of hepatitis A virus from childhood to adolescence and early adulthood, leading to increased symptomatology and risk of liver failure. 77 Widespread use of diphtheria-pertussis-tetanus vaccine in childhood has also been blamed for a rise in adult diphtheria and tetanus due to reduced natural boosting of immunity. 78 Steps to improve adult vaccination and overcome the barriers A 2012 report for the Organisation of Pharmaceutical Producers of India reported that stakeholders should "play a significant role in protecting the lives of children, adolescents and adults, through vaccination", but that the concept of adult vaccination in India is not established, with antibiotics or other treatments being used in adults in preference to vaccines. 79 This report had several recommendations that could help to improve adult vaccination, including improving awareness, incorporating adult vaccinations into regular Figure 3. How immune competence, risk of infectious disease, immunization programs, vaccine awareness, and vaccine coverage vary with age. checkups, and creating more affordable vaccine brands for adults (see green sections in Figure 2).
A study from seven European countries reported that adult vaccination (as per local guidelines) was less costly than infant/childhood/adolescent vaccines. 80 Also, that adult vaccination costs would likely be lower (on a per-person lifetime basis) than other commonly used secondary preventive measures (e.g. lipid-lowering drugs, bisphosphonates, antihypertensives, antihyperglycemics, and antithrombotics). 80 Various studies support the cost-effectiveness adult vaccinations (with or without age or risk restrictions), but data are mainly from high-income countries. [81][82][83][84] However, a recent study has estimated that introducing HPV vaccination among 10-year-old girls in India would cost US$15 per woman reached, $886 per cervical cancer case averted, and US $1,239 per death averted (undiscounted costs). 85 Further investigation into the cost-effectiveness of adult vaccines in lower-middle income countries such as India would be beneficial.
Ways to improve adult vaccination coverage in India are shown in the green sections in Figure 2. Unfortunately, this will take time. Even if national guidelines for adult immunizations are adopted, promoting these guidelines and the importance of adult vaccination would require considerable effort. The inclusion of free adult vaccinations in the Universal Immunization Program would be the ultimate goal, but policymakers would have to ascertain which VPDs and which risk groups (e.g. older adults, pregnant women, healthcare professionals, patients with underlying diseases) to target initially.

Surveillance of VPDs
Information on the adult burden of VPDs in India is lacking. Such knowledge of the Indian epidemiological profile would help in the assessment of public health needs and the impact of implementation of strategies. 86 Pilot initiatives to collect evidence on the VPD burden in adults could be a first step to providing useful insights into the current issues and possible solutions.

National guidelines
National guidelines would likely be based on the recommendations in Table 3. They would have to take factors such as health status, age, risk factors, and vaccination history into account. Table 4 shows which vaccines are recommended for various groups of adults in the US; 87 a similar table could be compiled for India. National multidisciplinary coordination and leadership of adult and life-course immunization will be vital, particularly as adults tend to visit a variety of healthcare professionals. 49

Education
Awareness of the benefits of adult vaccination should be promoted among healthcare professionals, along with distribution of new adult immunization guidelines. Campaigns to promote awareness among the public would also be required, perhaps using cartoons or comics to attract attention and curiosity, and to demystify vaccination. 88,89 As for current advice about a healthy diet and exercise, adult vaccination should be publicized on digital channels, at school, in the workplace, and in leisure facilities to help make them part of the social norm for a healthy lifestyle.
Pandemic influenza vaccination uptake in India has been reported to be higher among those who had seen information in the media. 61 Door-to-door delivery of pamphlets was also useful for people to know where to go to receive the vaccine. 61 In a study of Indian students, information about H1N1 influenza was more likely to have been received from the media (56%) or internet (41%) than from healthcare personnel (3%). 62 In a survey of parents in Mysore, willingness to accept HPV vaccination for their daughters was improved among those who knew that cervical cancer was serious and that HPV vaccination provided protection against cervical cancer, and those who perceived HPV vaccination to be safe. 90 These studies highlight the potential impact of education on vaccine uptake.
Healthcare workers can also contribute to increasing vaccination uptake by improving convenience, enhancing confidence, removing complacency, and being mindful of cultural acceptance (the "4Cs" model). 47 Provider recommendation and vaccination offer are key predictors of adult vaccination, but such recommendations are often not given, 48,91 hence providers should be encouraged to routinely assess their patient's vaccine needs. 48 This could also be improved by setting up provider reminders and vaccination standing orders; and reminders could also be provided to patients. 48

Life-course immunization
According to the WHO, a "life-course approach to health encompasses strategies across individuals' lives that optimize their functional ability, thereby enabling well-being and the realization of rights". 92 This involves looking at healthcare as a continuum through lifea dynamic and interconnected processas opposed to rigid life stages. 93 "Life-course immunization" focusses on the extension of vaccination from birth through childhood, adolescence, adulthood, and into older age. 47,94 This can involve catch-up vaccinations for those not immunized at the recommended ages and/or booster doses to address waning immunity. 47,94 Figure 3 shows how the immune system improves from birth to adulthood and then declines with older age (orange line), with a concomitant decrease and then rise in the risk of infectious disease (blue line). This highlights the importance of vaccination for older adults, who become increasingly likely to have immunosenescence. 47

Conclusions
We fear that, if not addressed, the burden of infectious disease is likely to have far-reaching devastating effects on humanity, especially with the increase in antibiotic resistance. The creation of awareness and public education are not sufficient to bring infectious diseases under control unless they are supported by clear recommendations. We believe that efforts should focus on VPDs, as there is already an available solution to this problem. All stakeholdersincluding experts (researchers) and policy makers (politicians and health professionals)should come together and ensure that the necessary steps are undertaken.
"Life-course immunization" has been adopted in many countries, as adult vaccination is an important contributor to healthy living. However, adult vaccination coverage in India is currently negligible, 15 due to a lack of national guidelines and perceived need. This failure to immunize adultsparticularly those with chronic conditionscan leave them vulnerable to infection and at increased risk of complications. Improving adult vaccination coverage in India, particularly among older adults, could help to reduce the burden of disease among those with chronic conditions by reducing hospital admissions, health costs, and mortality rates, and improving quality of life.