Review of the unmet medical need for vaccination in adults with immunocompromising conditions: An Indian perspective

ABSTRACT

Immunocompromised (IC) populations are at increased risk of vaccine-preventable diseases (VPDs). In India, the concern of VPDs in IC populations is particularly acute due to the prevalence of crowded living situations, poor sanitation and variable access to healthcare services. We present a narrative review of IC-related disease and economic burden, risk of VPDs and vaccination guidelines, based on global and India-specific literature (2000–2022). IC conditions considered were cancer, diabetes mellitus, chronic kidney disease, respiratory disorders, disorders treated with immunosuppressive therapy, and human immune deficiency virus (HIV). The burden of IC populations in India is comparable to the global population, except for cancer and HIV, which have lower prevalence compared with the global average. Regional and socioeconomic inequalities exist in IC prevalence; VPDs add to the burden of IC conditions, especially in lower income strata. Adult vaccination programs could improve health and reduce the economic impact of VPDs in IC populations.

Plain Language Summary

What is the context?

The population is aging, both globally and in India. Older age is associated with a weakened immune system. People with an immunocompromised (IC) status have a higher risk of contracting infections. The combination of these conditions greatly increases risk from infectious disease. A large percentage of infections, referred to as vaccine-preventable diseases (VPDs), could be avoided by vaccination. However, India-specific guidelines for adult immunization are limited and there is a low awareness of these recommendations among healthcare professionals and patients.

What is new?

The proportion of people with IC conditions in India is comparable to that seen in other countries. However, the risk of VPDs, such as influenza and bacterial pneumonia, is of particular concern in India; several factors, such as crowded living situation, poor hygienic conditions, and lack of access to healthcare may favor the spread of infections. The consequences of infections have the greatest impact on families with low income. Furthermore, only few India-specific guidelines exist with recommendations for adult immunization.

What is the impact?

There is a need to protect the growing IC populations against VPDs. The introduction of public healthcare and the experience from the nationwide COVID−19 immunization program in India provide an opportunity to extend adult vaccination programs covering other VPDs. Immunization programs could reduce the economic and disease burden associated with VPDs. Clear national guidelines and communication strategies are required to increase awareness of the benefit of vaccination.

GRAPHICAL ABSTRACT

KEYWORDS:

• Disease burden
• economic burden
• immunocompromised populations
• India
• vaccination guidelines for immunocompromised people
• vaccine-preventable diseases

Introduction

Vaccine-preventable diseases (VPDs) impose a substantial burden on patients, their families and the healthcare system. The burden of VPDs is however not uniformly distributed across the population, as infants, older people and people with an immunocompromised (IC) state are at higher risk of infectious diseases and associated complications. Over the past 50 years, IC populations have increased both in high and low- to middle-income countries, including India.^1–3 While some IC conditions are due to inherited dysfunctions in the immune system,⁴ most IC conditions arise secondary to other diseases or associated immunosuppressive therapies.⁵ The observed rise in IC prevalence can be explained partly by medical advances leading to IC populations living longer, the growing list of clinical indications for immunosuppressive therapies, and a globally aging population, who usually also have reduced immune function.^1,3,5–7 Thus, the increase in IC populations may be directly linked with age-related loss of immunocompetence or indirectly through the increased risk of non-communicable diseases (NCDs), such as cancer or diabetes, and some communicable diseases, such as human immunodeficiency virus (HIV) infection.^2,5

Impaired host defenses mean that IC adults are at increased risk of VPDs. The morbidity and mortality associated with these infections is also higher among IC adults.^8–11 Additionally, the severity and risk of adverse outcomes associated with VPDs are substantially increased in the IC population.^2,6,^12–14 If the growing population of IC adults are not protected against VPDs, increasing pressure will be put on the Indian health and social systems to meet healthcare demands due to both NCDs and VPDs.¹⁵ Despite vaccination being one of the most effective strategies for disease prevention, achieving high vaccination rates among IC adults remains a challenge in developing countries.^16–19 The reasons might be multifactorial, including poor infrastructure and access to healthcare services as well as low awareness of adult vaccination guidelines among healthcare professionals and patients.²⁰

While the implications of poor adult vaccination coverage have been discussed in detail for European and North American healthcare systems, there is less discussion in low- and middle-income countries such as India. The situation is particularly difficult in India, where much of the population is subject to crowded living situations, poor diet, lack of access to healthcare and substandard sanitation systems, increasing the risk for spread of infectious disease.^21,22 In addition, limited surveillance of VPDs in Indian adults means the burden of disease is likely to be significantly underestimated.²³ Therefore, compared with adult IC populations in high-income countries (who are already identified as at risk for VPDs), adults with IC conditions residing in India are likely to be at even greater risk of VPDs.

In the wake of the recent coronavirus disease 2019 (COVID−19) pandemic, India has an unprecedented opportunity to implement nationwide adult immunization programs leveraging existing COVID−19 infrastructure.²⁴ Political decisiveness is required to utilize the logistics and expertise acquired during the pandemic as long as knowledge and infrastructure are still effective and functional.

In this narrative review, we will discuss the risk of VPDs among IC adults in India and highlight the unmet needs to improve vaccination coverage in this population. In addition, we review existing vaccination policies globally and in India and their potential to alleviate economic and health-related disease burden.

Material and methods

In order to understand the risk of VPDs for IC adults in India, a narrative review was conducted guided by the following questions:

1. What is the prevalence of IC populations in India and the associated economic burden?

2. What are the risks and complications of VPDs in IC populations?

3. What are the recommendations and guidelines available for vaccination of IC populations globally and locally?

A literature search was conducted in two main databases, PubMed and Embase, using keywords and MeSH terms based on the questions above (Table 1). Due to the high degree of variation among different IC populations, we have focused our search on the following IC populations: cancer patients, patients taking immunosuppressive treatment (including transplant patients, rheumatological conditions), patients with diabetes, chronic kidney disease or HIV. There were no limits on the VPDs in the search strategy. The search was limited to publications from 2000 to 2022 and excluded the pediatric population, non-human and in vitro studies. Guidelines included were international vaccine recommendations and recommendations from the United States (US) and United Kingdom (UK), which are known to be consulted as reference documents in the conception of local vaccination guidelines in India. Publication with latest data on disease and economic burden were selected with preference given to studies conducted in the US and the UK to substantiate the vaccination guidelines that were selected.

Table 1. Search terms used for literature review.

Search category	Keywords
Geographic location^†	India OR Indian
Population	Adult
Immunocompromised conditions	Immunocompromised OR Immunosuppressed OR cancer OR malignancy OR neoplasm OR non-communicable disease OR chronic disease OR diabetes OR hypertension OR cardiovascular OR renal disease OR dialysis OR rheumatoid disease OR HIV OR AIDS
Vaccine preventable diseases	Vaccine Preventable Disease OR Herpes Zoster OR Zoster OR Shingles OR Influenza OR Flu OR Pneumonia OR Pneumococcal OR Hepatitis OR Pertussis OR HPV OR Varicella OR Measles OR Mumps OR Rubella

^†Searches were also run without geographic limit.

Results

A total of 94 publications were included in the narrative review, 33 describing disease and economic burden in IC populations (21 specific to India), 35 focusing on the risk of VPDs in IC populations (6 specific to India) and 33 publications presenting vaccination recommendations (7 specific to India). Seven publications were assigned to more than one category.

Disease burden of IC populations

India is projected to be the most populous country in the world very shortly.²⁵ The population of adults aged ≥60 years is growing at a rate three times faster than that of the total Indian population and will account for 19% of the worldwide population by 2050 according to projections.²⁶ This shifting age structure, alongside rapid urbanization, lifestyle transitions, deteriorating diets and pollution, has resulted in a growing burden of immunocompromising NCDs.^15,27–29 NCDs have become the primary cause of mortality in India, accounting for 60% of total deaths.^24,30 The most prominent NCDs contributing to the overall IC population in India include cancer; disorders treated with immunosuppressive therapy, such as autoimmune diseases and transplant patients; diabetes mellitus (DM) and chronic kidney disease (CKD). Communicable diseases, foremost HIV, add to the overall size of the IC population in India.

Risk factors for NCDs in India have been evaluated in a systematic review: the authors found a significant increase in overweight and obesity among adults during the observation period between 2005 and 2016. Obesity favors the development of cardiac disease and diabetes; on the other hand, alcohol and tobacco consumptions, risk factors for cancer and chronic liver disease, declined.¹⁵

Cancer incidence was estimated at 19.3 million new cases worldwide in 2020.³¹ Globally, 10.0 million deaths were attributed to cancer.^31,32 While cancer incidence in India is still markedly lower compared with global average (1,751 vs 3,943 per 100,000 people in India vs globally in 2019⁹), it is expected to almost double by 2040.³³ Based on national registry data, significant heterogeneity in cancer burden in India was demonstrated, with the highest burden observed in the North and Northeast, and with men being proportionally more affected than women.^34,35 Cancer contributes substantially to the number of IC adults in India (Figure 1; Table 2); not only can cancer itself cause a state of immunosuppression, but non-targeted, cytotoxic cancer therapy often compromise the immune system.⁵³

Figure 1. Prevalent cases/100,000 people globally and in India −2019.

HIV: human immunodeficiency virus. Source: Institute for Health Metrics and Evaluation. GBD compare, Viz hub.⁹

Table 2. Epidemiology and risk of infection in immunocompromised populations in 2019.⁹.

	Risk of VPDs
IC conditions combined	Risk for all-cause pneumonia and invasive pneumococcal disease is 3.6-fold and 4.6-fold increased, respectively, in IC populations compared with the general population.^Citation36 High risk of developing serious influenza-related complications with influenza infection in IC population (including HIV, ongoing malignancies, hematologic and solid organ transplant, high-dose corticosteroid recipients, pregnant women and children).^Citation37 Patients with IC and influenza are at higher risk of co-infections with other bacteria and fungi, development of antiviral resistance and have increased morbidity and mortality.^Citation37 Influenza is linked to the commonest causes of severe disability in older adults, including stroke, congestive heart failure and pneumonia.^Citation6 Among different IC conditions, the highest predisposing risk for HZ was observed in people with kidney transplant (8.46-fold higher risk), lymphoma (8.23-fold higher risk), and treatment with immunosuppressive drugs such as infliximab for rheumatoid arthritis (7.10-fold increased risk).^Citation38 Based on a systematic literature search, predisposing factors for HZ in India included HIV, T2D, prolonged steroid use, and malignancies.^Citation39
Epidemiology and risk of infections in specific IC conditions
	Incidence^a New cases/100,000 (Lower; Upper bound)		Prevalence Prevalent cases/100,000 (Lower; Upper bound)		All-age deaths Deaths/100,000 (Lower; Upper bound)
IC condition	Global	India	Global	India	Global	India	Risk of VPDs
Neoplasms/Cancer	3,943.11 (3,342.17; 4,712.35)	1,751.16 (1,448.39; 2,163.64)	6,273.42 (5,400.04; 7,261.97)	2,571.89 (2,110.94; 3,085.19)	130.27 (121.65; 137.8)	67.06 (58.43; 77.52)	Structural derangements and changes in immunological responses to pathogens increase the risk of bacterial infections of the respiratory tract.^Citation40 High rates of hospitalizations, pneumonia and death with influenza infection.^Citation41,Citation42 Significant increased risk of invasive meningococcal disease.^Citation43 Cancer patients, especially those with hematological malignancies have significantly reduced seroprevalence against VPDs, putting them at higher risk of infection.^Citation44 Presence of malignancies was identified as predisposing factor or co-morbid conditions in HZ patients.^Citation39
Diabetes mellitus	287.42 (266.23; 310.94)	310.49 (282.98; 342.19)	5,943.49 (5,473.04; 6,435.97)	6,139.82 (5,550.94; 6,782.82)	20.05 (18.68; 21.33)	19.64 (17.08; 22.75)	The risk of hepatitis B infection is 43% higher in patients with T2D.^Citation45 Diabetes is an independent factor in mortality of patients with invasive pneumococcal infections, which is approximately three times higher in diabetic patients compared with non-diabetic peers.^Citation46,Citation47 People with T2D are six times more likely to be hospitalized during an influenza endemic.^Citation46 Diabetes mellitus was identified as pre-disposing or co-morbid conditions in people with HZ.^Citation39
Chronic kidney disease	245.39 (226.9; 265.18)	155.43 (141.25; 169.94)	9,011.92 (8,401.27; 9,577.82)	8,285.22 (7,666.46; 8,931.4)	18.45 (16.98; 19.7)	16.03 (13.77; 18.59)	Decreased kidney function led to increased healthcare resource use associated with influenza.^Citation48 In patients with reduced kidney function, influenza vaccination reduced the odds ratio for pneumonia or influenza-related hospitalization (OR: 0.86; 95% CI: 0.79–0.93).^Citation48
Rheumatoid arthritis	13.89 (12.61; 15.24)	16.03 (14.47; 17.72)	240.18 (219.13; 264.09)	216.78 (196.23; 239.17)	0.57 (0.44; 0.67)	0.89 (0.59; 1.17)	Excess mortality observed in patients with RA might be due to several factors, including increased risk of infectious diseases.^Citation49 Bacterial infections of the lung are more common in RA, which might be linked to weakened immune system, especially in patients being treated with corticosteroid and/or antitumor necrosis factor, or because of interstitial lung disease, which is common among RA patients.^Citation49 The risk of bacterial, tubercular and fungal infections increases as disease severity increases in RA patients.^Citation49 Increased steroid use was identified as predisposing factor for HZ.^Citation39
HIV	25.71 (22.76; 29.2)	5.28 (3.2; 8.31)	476.23 (454.27; 502.19)	131.33 (117.38; 147.5)	11.16 (10.16; 12.87)	3.33 (2.95; 3.84)	TB is the leading cause of death in patients with HIV infection.^Citation50 Higher mortality from liver complications with hepatitis B infections.^Citation51,Citation52 HIV was identified as a risk factor for HZ.^Citation39

^aNumber of new cases in 2017.

CI: confidence interval; HIV, human immunodeficiency virus; HZ: herpes zoster; IC: immunocompromised; OR: odds ratio; RA: rheumatoid arthritis; T2D: type 2 diabetes; TB, tuberculosis; VPD, vaccine preventable disease.

Similarly, NCDs treated with immunosuppressive therapy increase the risk of infectious disease. Autoimmune disorders, such as rheumatoid disorders, multiple sclerosis (MS), inflammatory bowel disease (IBD), as well as people with asthma and transplant recipients are in general treated with immunosuppressive therapy. Based on a survey conducted at rural and urban centers in India, point estimates for different rheumatoid disorders varied between 0.02% (systematic lupus erythematosus [SLE]) and 4.39% (osteoarthritis), highlighting the substantial burden imposed by these disorders.⁵⁴ Incidence and clinical manifestation of SLE vary across countries, but some evidence suggests that morbidity and mortality are higher in people with Asian and African ancestry.⁵⁵ In India, clinical management of rheumatoid disorders is still in its infancy, with only few specialized centers providing care for people with rheumatoid disorders.⁵⁶ However, with the increased use of immunosuppressive therapy, the concern for infections in general, and tuberculosis in particular, has sharpened, adding to the burden of rheumatoid disorders.⁵⁶ Organ transplantation is dominated by people with end-stage renal kidney disease, with an estimated 7,500 people undergoing kidney transplant in India, followed by liver, heart and lung transplants.^57,58 In addition, number of patients undergoing hematopoietic stem cell transplantation is steadily increasing every year, adding to the population being treated with immunosuppressive therapy.

The high-income Western lifestyle, characterized by poor nutritional choices and sedentary habits, has spread globally as income has risen, leading to an increase in obesity, type 2 diabetes (T2D) and cardiovascular diseases. In India, obesity affects more than 135 million individuals according to serial national surveys, but prevalence rates highly depend on age, gender, urban vs rural setting, socioeconomic status and geographical location.³⁰ Obesity is higher in women compared with men and higher in urban than rural settings: 22.5%, 45.6% and 57.4% of rural, urban low-class and urban middle-class women were considered obese, respectively.³⁰ Interestingly, Asian Indians tend to have more abdominal fat compared with Caucasians, increasing the detrimental effect of excess body weight on metabolic syndrome and cardiovascular risk factors. As a consequence, India is seeing a rise in its T2D population from ~69 million to an estimated 140 million in 2040.³⁰ Diabetes is also a major risk factor for chronic kidney disease (CKD), which is expected to increase in prevalence.⁵⁹ Malnutrition, poor sanitation and nephrotoxins are additional risk factors for CKD in India. However, the true burden of CKD is ill described in the absence of a national registry and the scarcity of centers dedicated to patients with renal disease.⁶⁰ Obesity, metabolic syndrome, T2D and CKD can all have deleterious effects on the immune system and account for a large number of IC adults in India (Figure 1).^8,61 Optimal disease control often improves a patient’s immune function; however, in India many cannot afford suitable treatment.^5,60

Among communicable diseases, HIV is of particular concern, as the virus attacks CD4⁺ T cells, which are crucial for the proper functioning of the immune system.⁵ Globally, approximately 38 million people live with HIV and in 2021, there were an estimated 1.5 million new HIV cases.^5,62,63

An estimated 2.14 million people are living with HIV in India, representing the third largest HIV population of any country worldwide.⁶⁴ While a slight downward trend in HIV incidence was observed in recent years, large variations were observed between districts, with incidence positively correlating with population size, density, urbanization and at-risk populations.^64–66 At the same time, prevalence is plateauing or increasing, likely due to improved clinical management leading to an increase in life expectancy.⁶⁷ The highest burden in terms of HIV prevalence was observed in the Northeast, particularly in the states of Mizoram, Nagaland and Manipur, all with prevalence >1% compared with the national prevalence of 0.22% in the adult population.^65,68

Prevalence estimates (cases per 100,000 people) for different IC conditions are on a par with global estimates, except for cancer and HIV (Figure 1). Together, the increase in NCDs and HIV infection along with the large and aging Indian population give rise to high levels of immunosuppression and thus aggravate susceptibility to infection in adults.

Economic burden of IC populations

The continuous increase in IC populations is a global problem, but India is more economically constricted when it comes to dealing with the health issues compared with high-income countries.⁶⁹ Only 1.5% of the overall global domestic product (GDP) is dedicated to public healthcare, while the total of public and private investments amounts to 4% of overall GDP.⁶⁹ Furthermore, healthcare policies in India are complex, as they need to deal with regional and social disparities, inequalities in access to healthcare and a large diversity in health-related problems originating both from infectious diseases and NCDs.⁷⁰

Despite some progress being made in the inauguration of healthcare programs, public health improvement has not advanced in India as in some other countries with similar GDP.⁷⁰ This could be due to competing interests on the political agenda, such as building infrastructure to improve sanitation and access to drinking water. Another possible reason lies in the deeply rooted Indian tradition that views personal care as a responsibility of family and kinship. Only a small proportion of the population has health insurance.³⁰ A large proportion of healthcare expenditure is paid out of pocket, often pushing people with IC conditions and their families into financial crisis and debt.^69,71,72 With the introduction in 2018 of the Ayushman Bharat Yojana health insurance scheme for Indian’s economically disadvantaged population, it is hoped that the financial strain imposed on families will be reduced with the goal of improving healthcare access for the most vulnerable and poor.⁷³

In India, annual direct and indirect costs for diabetes care were estimated at US$ 31.9 billion in 2010 and this economic burden is predicted to rise to nearly US$ 150 billion in 2030.³⁰ People with T2D from the low-income strata are estimated to spend 25% to 35% of their annual income on diabetes care.³⁰ In case of complications and hospitalizations, these costs can increase several-fold. Another aspect to consider is that Indians often develop metabolic syndrome and T2D at a younger age compared with Caucasians.³⁰ Increased T2D-related morbidity and mortality occur during peak years of their productive life and have profound effects not only on their personal finances and those of their families but also on the individual’s contribution to national economic growth.

The same holds true for HIV. In a household survey conducted in people diagnosed with HIV in India, HIV prevalence was highest in individuals 25–35 years old, representing people in the active labor force.⁷¹ Twenty percent (20%) of HIV+ men and 10% percent of HIV+ women lost their employment. However, approximately 30% of women who were unemployed prior to HIV diagnosis, started working after diagnosis, which might reflect their obligation to cope with healthcare expenditures. Individual responses showed that patients who lost their jobs, also lost their savings and had to sell their possessions and take on debt to cover medical bills.⁷¹

Burden of VPDs in IC populations

VPDs in adults impose a substantial burden to patients and the healthcare system, especially in the absence of life-course immunization programs.⁷⁴ Several studies have shown that infectious diseases lead to higher average costs per episode in patients with IC conditions compared with the general population.^36,75,76 In a retrospective healthcare database study conducted in the US, invasive pneumococcal disease (IPD) led to costs of $58.5 million per 100,000 patient years in people at high risk, including individuals with IC conditions and HIV, which were 23.4-fold higher compared with the general population.^74,76 Incremental costs in the IC populations are driven by a higher probability of severe disease and complications, more frequent and longer hospitalization and need for additional specialized care (Table 2).^37,74 In general, the risk of VPDs and the associated morbidity and mortality are high among IC adults (Table 2).^8–11

In a retrospective database study, conducted in the US, the risk of all-cause pneumonia and IPD was respectively 3.6 and 4.6-fold higher in IC populations compared with the general population.³⁶ In an English cohort study, the overall incidence of herpes zoster (HZ) in IC adults was 7.77/1000 person-years compared with 6.21/1000 person-years in immunocompetent adults.⁷⁷ This study also reported that older IC adults (≥80 years) had an almost five-fold greater risk of developing postherpetic neuralgia (PHN) compared with younger IC adults (18–49 years); PHN is a significant complication of HZ infection, associated with persistent pain and significant reduction in quality of life.⁷⁷ HZ epidemiology is similar in Asia with a lifetime risk of approximating 30% and a rising trend, most likely due to an aging population and increased use of immunosuppressive drugs.³⁸ Invasive meningococcal disease (IMD) has been reported in India both in endemic and epidemic settings, such as in mass gatherings during Haj pilgrimage.^78,79 While Neisseria meningitidis is responsible for only approximately 1.9% of bacterial meningitis in all age groups confounded, the true burden of IMD in India is probably underestimated due to incomplete reporting.⁸⁰ In a French case–control study, the risk of IMD-related hospitalization was up to 39-fold higher in patients with primary immunodeficiency, and up to five-fold higher in people with chronic medical conditions.⁴³

In cancer patients, bacterial pneumonia is the most common infection. Cancer patients have a 40 to 50-fold increased risk of IPD compared with healthy adults.⁸¹ Pneumonia frequently leads to hospitalization and need for mechanical ventilation.^40,41 In a prospective study conducted in cancer patients admitted to the hospital with pneumonia, 81% required mechanical ventilation and 75% presented with septic shock.⁴¹ Mortality rates were 45.8% in people admitted to the ICU and 64.9% in patients admitted to the general ward.⁴¹ Cancer patients are also at increased risk of influenza and HZ and associated complications (e.g., PHN).⁸¹

Adults with diabetes are six times more likely to be hospitalized during an influenza episode and are almost three times more likely to die of pneumonia complications compared with those who do not have diabetes.⁴⁶ In a multicenter, observational cohort study, diabetes was found to be an independent factor for mortality in patients with IPD (hazard ratio: 1.91; 95% confidence intervals: 1.23–3.03; p = .006).⁴⁷ In addition, higher hepatitis B infection rates were observed among people with diabetes compared with nondiabetic people.⁴⁵

CKD is a risk factor for influenza-related hospitalization, especially in people with glomerular filtration rates <30 mL/min/1.73 m².⁴⁸ A study in India examined the proportion of risk factors in patients with IPD. Among 233 patients with invasive pneumococcal disease, 151 (62%) had at least one risk factor for pneumococcal infection, with the most common ones being CKD (n = 37), malignant disease (n = 31), diabetes (n = 27) and immunosuppressive treatment (n = 32).⁸²

People with HIV are at increased risk of severe disease from both hepatitis A (HAV) and B (HBV) infection.^51,83,85 HBV co-infection in patients with HIV results in higher rates of chronicity and occult HBV (HBV-DNA positivity in the absence of the hepatitis B surface antigen) increased end-stage liver disease, higher mortality from liver complications and decreased response to treatment.⁵¹ This co-infection is particularly concerning in India, where prevalence of HIV-HBV co-infection is 8.3%.⁵¹ The risk of bacterial and viral respiratory tract infections, as well as IMD is higher in people with HIV compared with the general population.^74,84 HIV-positive individuals are at higher risk of developing serious influenza-related complications when they contract influenza, especially those who have a very low CD4⁺ cell count (indicating a highly suppressed immune system) or those who are not taking antiretrovirals.^37,85,86 Similarly, in a retrospective study, HIV patients with IMD were 5.3-times more likely to have CD4⁺ counts <0.2 × 10⁹ cells/L than those without IMD.⁸⁴ In India, the adherence to antiretrovirals is low, as many people cannot access suitable clinics; in 2021, only 65% of Indians living with HIV were receiving treatment.⁸⁷ As a result, many people with HIV in India may be at high risk of severe influenza-related complications.

A recent report suggested that in India, 95% of deaths due to VPDs occur in adults,⁸⁸ however, India-specific data regarding burden of VPDs in IC populations remain limited. As vaccines are one of the most cost-effective health interventions available, the implementation of successful adult immunization programs is imperative, particularly for the most vulnerable adult populations.^17,18,46,88

Vaccination in IC population

Vaccination among IC adults can reduce the incidence and severity of VPDs, as well as rate of VPD-related complications, subsequently limiting the socioeconomic burden and contributing to healthy aging.^74,89 A systematic review assessing the cost-effectiveness of numerous adult vaccinations between 1980 and 2016 reported a favorable cost-effectiveness profile for most adult vaccinations when compared with no vaccinations. Cost savings and cost-effectiveness ratios of ≤$50,000 per quality-adjusted life years were reported for the influenza and pneumococcal vaccinations.⁹⁰ Several developed countries, including Australia, Germany and the UK have life-long immunization programs in place. Increased adult vaccination was shown to reduce the risk of hospitalization, hospitalization lengths and mortality.⁷⁴

Yet, adult vaccination in India is an overlooked and poorly communicated issue, leaving a large population of IC adults vulnerable to infection.²³ There are only few India-specific guidelines providing recommendations for adult immunization schedule that focus on IC populations.^88,91,92 Therefore, consultation of recommendations issued for other regions and countries is useful in order to gain a complete picture of immunization schedules for IC populations. Available vaccination guidelines vary between countries but agree on the need for specific prevention strategies for at-risk populations including people with IC conditions (Table 3). Whenever possible, vaccines should be administered prior to immunosuppression or administration should be delayed until immune recovery.⁸¹ This is particularly relevant to individuals due to start immunosuppressive treatment when it is advised that inactivated vaccines should be given at least 2 weeks before the start of treatment onset.⁹³ In cancer patients not immunized prior to therapy, vaccination should occur at least 3 months after discontinuation of immunosuppressive therapy.¹¹³

Table 3. Recommendations for vaccinations in adults with immunocompromising conditions provided by various guidelines across the world.^{2,12,91–93,94–112}.

Vaccination	Guidelines		Immunocompromising condition
			PID^a	SID
				HIV		Cancer	Diabetes	CKD	HSCT	SOT
Influenza	Global	WHO	All IC adults
	US	CDC	Inactivated vaccine				Inactivated vaccine/ precautions for use of LAV		Inactivated vaccine
	UK	PHE	All (the degree of immunosuppression should be assessed before administering LAV)
	India	API	Not currently recommended due to lack of reliable epidemiologic data on the burden of influenza
		IMA	All (LAV are contraindicated in severely IC patients)						4–6 months after transplantation		All
		ICS:NCCP	All IC adults
Pneumococcal	US	CDC	All with congenital immunodeficiency disorders	All (PCV13 followed by PPV23)		All with blood cancers, general malignancies and radiation therapy recipients	All (PPV23)	All (PCV13 followed by PPV23)	All (PCV13 followed by PPV23)	All (PCV13 followed by PPV23)
	UK	PHE	All (PPV23)	All (PPV23) Severely IC (PCV13 followed by PPV23)		All with blood cancers, or chemotherapy recipients (PCV13 followed by PPV23 in severely IC)	All (PPV23)	All (PPV23)	PCV13 should be offered 9–12 months following transplantation	All (PCV13 followed by PPV23 in severely IC)
	India	API	Not currently recommended due to lack of evidence on effectiveness in high-risk populations
		IMA	All (PCV13 followed by PPV23)	All (PCV13 followed by PPV23)	All (PCV13 no less than 3 months after chemotherapy followed by PPV23)		All (PCV13 followed by PPV23)	All (PCV13 followed by PPV23)	All (PCV13 3–6 months after transplantation followed by PPV23 12 months after transplantation)		All (PCV13 followed by PPV23)
Herpes zoster	Global	WHO	Usually contraindicated in congenital/acquired immune deficiencies; however, due to the increased severity of varicella in certain groups, herpes zoster vaccine is indicated in IC adults ≥50 years of age
	US	CDC	RZV vaccine has been approved for use in patients ≥18 years of age that are IC
	UK	PHE^b	RZV recommended in patients 70–79 years of age with primary/acquired cellular and combined immune deficiencies	RZV recommended in patients 70–79 years of age with a current CD4 count <200 cells/μL		RZV recommended in patients 70–79 years of age with acute and chronic leukemia, aggressive lymphoma and other hematologic malignancies	–	–	RZV in patients 70–79 years of age who have received a transplant in previous 24 months		RZV recommended in patients 70–79 years of age who have had immunosuppressive therapy in past 6 months
	India	API	Not currently recommended due to lack of reliable epidemiologic data on the burden of HZ
		IMA	–	–		–	–	–	–		Not recommended
Hepatitis B	Global	WHO	All IC adults
	US	CDC	–	All		–	All 19–59 years of age with diabetes or at physician discretion in adults ≥60 years of age	All	All		–
	UK	PHE	–	All		–	–	Patients on dialysis or with chronic renal failure for whom the need of dialysis is anticipated	–		–
	India	API	Recombinant vaccine is administered at 0, 1, 2 and 6 months
		IMA	–	All		All	–	–	6 months after transplantation		All
Tdap	Global	WHO	All IC adults
	US	CDC	All IC adults
	UK	PHE	All IC adults
	India	IMA	–	All		One dose ≥3 months after chemotherapy	–	–	TD to be given 6–12 months after transplantation		Consider booster TD post-transplant
HPV	Global	WHO	All IC adults
	US	CDC	All ≤26 years of age; use in adults 27–45 years of age at HCP discretion	All ≤26 years of age; use in adults 27–45 years of age at HCP discretion		All ≤26 years of age; use in adults 27–45 years of age at HCP discretion	All ≤26 years of age; use in adults 27–45 years of age at HCP discretion	All ≤26 years of age; use in adults 27–45 years of age at HCP discretion	All ≤26 years of age; use in adults 27–45 years of age at HCP discretion		All ≤26 years of age; use in adults 27–45 years of age at HCP discretion
	UK	PHE	A 3-dose schedule should be offered to those IC at time of vaccination
	India	API	All IC adults
		IMA	All (3 doses recommended)	All (3 doses considered)		All IC (3 doses recommended)			6 months after transplantation		All IC adults (3 doses recommended)
MMR	Global	WHO	–	All Unless severely immunocompromised		–	–	–	–		–
	US	CDC	Not recommended in severe antibody and phagocyte deficiencies	All born in 1957 or after with a CD4^+ count <200 cells/μL		–	Consider in adults born in 1957 or later	All born in 1957 or later	Not recommended in IC individuals		–
	UK	PHE	Not recommended for IC individuals	HIV-positive if not IC or moderately IC		Not recommended for IC individuals
	India	API	Not recommended in severely IC adults
		IMA	Not required for B-lymphocyte deficiencies and contraindicated for T-lymphocyte deficiencies	Not if severe immune suppression (CD4% T cells < 15%)		All	–	–	4–8 weeks after transplantation		Not recommended
Varicella(chickenpox) (chickenpox)	Global	WHO	Usually contraindicated in persons with congenital/acquired immune deficiencies; however, due to the increased severity of varicella in certain IC populations, varicella vaccination (2 doses) may be considered
	US	CDC^c	Contraindicated in most PIDs but recommended for impaired humoral immunity	>8 years of age with a CD4^+ count ≥200 cells/μL		Not recommended in patients with leukemia/ lymphoma affecting bone marrow or lymphatic system	Consider in adults with diabetes	All born in 1980 or later	Not recommended		Not recommended for those on high dose immunosuppressive treatment
	UK	PHE	Vaccine should not be given to IC adults
	India	API	–	2 doses in all with CD4^+ count >200 cells/µL		Not recommended in patients with cancer affecting bone marrow or lymphatic system or on high dose immunosuppressive treatment	–	–	–		Not recommended for those on high dose immunosuppressive treatment
		IMA	–	Not if severe immune suppression (CD4% T cells < 15%)		All	Recommended for those with inborn errors of metabolism	–	2 doses 4–8 weeks after transplantation		Not recommended
IMD	Global	WHO	Recommended for all individuals with immunodeficiency, including asplenia, terminal complement deficiencies, or advanced HIV infection. Choice of vaccine depends on the locally prevalent serogroup
	US	CDC	Conjugate MenACWY-CRM or MenACWY-D and MenB vaccine^d	MenACWY vaccine		No specific recommendation for meningococcal vaccines; however, it is noted that ‘Other vaccines that are universally or routinely recommended should be given if not contraindicated’
	UK	PHE	MenACWY and MenB vaccines^d	MenB, two doses one month apart and MenACWY vaccines, two doses at least 2 months apart. Re-immunization to be considered as individuals may not make full antibody response		No special recommendation
	India	API	Meningococcal vaccine is recommended in all immunocompromised individuals.
		IMA	Conjugated quadrivalent vaccine in adults up to 55 years of age

^aAssumed where guidelines recommend for IC adults, PID are included; ^bSupply of RZV is limited so individuals 70–79 years of age with lower levels of immunosuppression should be offered LAV; ^cWithout evidence of immunity against varicella. ^din persons with functional or anatomic asplenia and persons with persistent complement component deficiency.

API, the association of physicians of India; CD4, cluster of differentiation 4; CDC, Centers for Disease Control and Prevention; CKD, chronic kidney disease; HCP, healthcare provider; HPV, human papillomavirus; HSCT, hematopoietic stem cell transplant; HZ, herpes zoster; IC, immunocompromised; ICS:NCCP, Indian Chest Society and National College of Chest Physicians; IMA, India Medical Association; IMD: invasive meningococcal disease; LAV, live attenuated vaccine; MMR, measles, mumps and rubella; PCV13, 13-valent pneumococcal conjugate vaccine; PPV23, 23-valent pneumococcal polysaccharide vaccine; PHE, Public Health England; PID, primary immunodeficiency disease; RZV, non-live recombinant zoster vaccine; SID, secondary immunodeficiency disease; SOT, solid organ transplant; Tdap, tetanus, diphtheria and pertussis; TD, tetanus and diphtheria; UK, United Kingdom; US, United States; WHO, World Health Organization.

Even though vaccine effectiveness may be lower in IC patients compared with the general population, vaccination may still confer protection and reduce morbidity and mortality of VPD.⁸¹ The immune response in severely immunocompromised individuals upon vaccination may be insufficient; re-immunization of individuals with inadequate immune response or vaccination of family members for indirect protection needs to be considered in these individuals.^2,114 In cancer patients, the immunogenic response may vary widely, depending on the type of cancer, chemotherapeutic agents and underlying humoral response.⁴⁰ In general, most guidelines do not recommend the use of live attenuated vaccines (LAVs) in IC adults; however, in some patients who are not severely IC, LAVs may be considered (Table 3).¹¹⁵ In India, there is a lack of comprehensive and nationally adopted vaccination guidelines for IC adults.²³ When vaccination guidelines do exist, they are often based on information issued by Western countries (e.g., US, UK), which does not always apply to the Indian population, which presents with different epidemiology and risk factors for VPDs.^23,38

Discussion

IC populations in India are predicted to increase over the next decades due to a demographic shift toward older population, rapid urbanization combined with poor living standards and pollution.^15,70 This shift is occurring at a faster pace than that observed in Western countries, which leaves little time for adaptation to new healthcare and socioeconomic challenges.³

IC conditions combined with an increased risk of VPDs impose a high burden on patients and their families, as well as the healthcare sector. The burden of IC is not distributed uniformly in India. Some geographic regions and socio-economic strata have significantly higher prevalence rates compared with others. For example, cancer and HIV prevalence were highest in North and Northeast regions. In addition, low-income households bear a proportionally higher economic burden due to IC conditions compared with the middle- and high-income classes. Most of the disease burden due to IC conditions occur when people are in their peak working and earning years, thus affecting productivity and economic development.¹¹⁶ Preventative measures, such as immunization programs, could reduce the burden of illness in IC adults, thereby minimizing the impact on working hours and the economy.

Mass immunization programs are effective strategies to lower the disease and economic burden of VPDs both at the individual level and from a health-economic perspective. Despite undoubted benefits of adult immunization, vaccination coverage remains suboptimal even in high-income countries. For example, the World Health Organization (WHO) target for influenza vaccination coverage was 75% among elderly populations by 2010 in Europe. This target was achieved by only one country (the Netherlands).¹¹⁷ In the US, VPDs in adults still incur costs of $27 billion annually.⁷⁴ Barriers to vaccination include limited healthcare encounters, lack of specific recommendations and limited awareness of health benefits conferred by vaccination. An additional challenge in vaccinating people with IC conditions concerns the varying levels of altered immunocompetence. Individuals with a severe immunocompromised status may have an inadequate immunogenic response to vaccines; the level of altered immunocompetence should be determined prior to vaccination by the physician, rendering vaccination strategies even more complex.² In India, substantial economic inequalities and personal beliefs represent additional roadblocks to the deployment of effective adult immunization programs.

It has been reported that socioeconomic status is strongly correlated with vaccination status; in the richest areas of India, the vaccination coverage is indeed two times higher compared with the poorest areas.^118,119 India’s universal immunization program covers eleven vaccines, but these are mainly for children and pregnant women.¹²⁰ Therefore, IC adults in India have to pay for their vaccinations themselves, which places a huge additional financial burden on the Indian population for whom the cost of IC treatment is already high; This acts as a significant barrier to the acceptance of vaccines.¹²¹ A lack of education about the role of vaccination and concerns about vaccine efficacy and potential side effects are additional factors contributing to the poor rates of adult vaccination.^16,122 In India, one survey reported that 68% of adults were not aware of the vaccines recommended for them and 38% of adults perceived immunization as being for children only.^23,123

Cultural and religious factors also pose a barrier to vaccination among IC adults in India. Western biomedicine and indigenous medicine co-exist and adherence to either of these is distributed along a wide spectrum. Within some communities, there is little acceptance of Western medicine, including vaccinations.¹²⁴ However, if vaccine education is delivered in a culturally responsive and sensitive way, there is still the possibility to reach people in these communities. An excellent example of this was the involvement of religious leaders in garnering support for the polio vaccination, which contributed to India being declared polio-free in 2014 by the WHO.^124,125 The COVID−19 pandemic has highlighted the urgent need to increase the coverage of adult vaccinations, particularly for the IC adult population. The success of the national COVID−19 immunization campaign could be harnessed to improve access to other adult vaccinations using existing infrastructure and expertise. Effective information campaigns, use of existing infrastructure from the universal immunization program and the development of a digital platform to register and book vaccination slots led to India having one of the highest Covid-19 vaccination coverage.¹²⁶

There are several limitations to this study. India-specific prevalence and incidence data of IC conditions are limited in the absence of nationwide disease-specific registries. Apart from HIV, for which nationwide screening programs have been instituted, IC conditions are likely underreported.³⁹ Data regarding risk factors and the economic burden of VPDs in IC populations in India are scarce and most of the information reported in this review are from studies carried out in North America and Europe. While some of the findings can be reasonably assumed to translate to the Indian context, others might not, due to epidemiological, genetic and socioeconomic differences. Further studies are needed to assess the economic impact of VPDs in a wider range of IC populations in India and to assess the benefit of adult vaccination programs.

Conclusion

IC populations in India pose an increasing challenge for the healthcare and social welfare system. Vaccines are one of the most cost-effective health interventions available and the implementation of successful adult immunization programs is imperative, particularly for the most vulnerable adult populations. A rapidly growing older population, inequalities in healthcare access and the absence of a public immunization program targeting the adult population complicate the task of providing nationwide immunization against VPDs. Following the COVID−19 pandemic, India has an unprecedented opportunity to leverage the infrastructure put in place for the COVID−19 vaccination campaign to provide nationwide immunization coverage against other VPDs.

Author contributions

All authors participated in the design or implementation or analysis, interpretation of the study, and the development of this manuscript. All authors had full access to the data and gave final approval before submission.

All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The work described was carried out in accordance with the recommendations of the International Committee of Medical Journal Editors for conduct, reporting, editing, and publication of scholarly work in medical journals.

Acknowledgments

The authors thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Katrin Spiegel, on behalf of GSK, provided medical writing support.

Disclosure statement

Peter San Martin is employed by GSK. Mark Doherty and Yashpal Chugh are employed by and hold shares in GSK. Peter San Martin, Yashpal Chugh and Mark Doherty declare no other financial and non-financial relationships and activities. Ashok Vaid and Neha Rastogi, declare no financial and non-financial relationships and activities and no conflicts of interest.

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Additional information

Funding

GlaxoSmithKline Biologicals SA funded this literature review and took in charge all costs associated with the development and publication of this manuscript.