Expanded spectrum of varicella disease and the need for vaccination in India

ABSTRACT

Varicella vaccine was first licensed in Japan and South Korea in 1989 for use in healthy children and was introduced in US in 1995. So far, 29 countries have adopted varicella vaccine in their universal immunization program (UIP). No Asian country, India included, has adopted the varicella vaccine as part of their UIP. The extra-cutaneous sites for VZV diseases are central nervous system and gastrointestinal tract, the expanded disease spectrum includes vasculopathy, myelitis, inflammatory bowel disease, perforated ulcers, and gastritis. The actual disease burden of varicella is not known as most of the infected individuals may not visit the physician. The amplifiable VZV DNA will not always be detectable in cerebrospinal fluid (CSF) samples in protracted illnesses such as vasculopathies, but demonstrable anti-VZV IgG in CSF has diagnostic value. The World Health Organization (WHO) position paper 2014 recommends two doses of varicella and zoster vaccines in targeted population. In India, varicella vaccine is not included in the UIP due to the cost and the belief that lifelong immunity occurs following primary infection. The expanded spectrum of VZV disease and the mounting body of evidence, however, suggest the need for both varicella and zoster vaccines in routine immunization schedule.

KEYWORDS:

• Varicella zoster virus (VZV)
• chickenpox
• herpes zoster
• varicella vaccine
• zoster vaccine
• disease spectrum of VZV

Introduction

Varicella and zoster are both vaccine-preventable diseases. Chickenpox (varicella), caused by varicella zoster virus (VZV) is considered to be a self-limiting benign childhood disease characterized by generalized maculopapular rash. Reactivation of latent VZV causes herpes zoster (HZ). HZ manifests with localized rash and pain. Both occur in immunocompromised and immunocompetent individuals. HZ pain is usually reported to be very severe and intense, persisting for months and sometimes even years. The most common complication of HZ is post-herpetic neuralgia (PHN) which occurs in about 10–20% of cases. VZV infection is ubiquitous and the risk of reactivation of VZV is approximately 30% in the United States (US) and Asia Pacific (APAC). HZ is common in the US, with over one million cases occurring every year. In 2020, 14.9 million cases of HZ occurred in people >50 years of age worldwide, and it is estimated to increase to 17 million in 2025 and 19.1 million in 2030 due to the aging population.¹

Varicella vaccine

Takahashi et al. first described a live vaccine for the prevention of varicella in 1974. All the currently available live varicella vaccines were derived from the parent Oka strain, which was first isolated from a 3-year-old boy with varicella from Japan. The Oka strain was passaged 11 times in human embryonic lung fibroblast at 34°C, 12 times in guinea pig fibroblast cells at 37°C and 7–8 times in MRC-5 cells at 37°C. The final sonicated passaged viral product with 1500–5000 plaque forming unit (pfu) constitutes each dose of the vaccine.² Varicella vaccine was first introduced for use in healthy children in Japan and Korea in 1989 but not as part of the National Immunization Program (NIP). The first use of the vaccine in USA was in 1995 as part of universal immunization program (UIP).³ The World Health Organization (WHO) position paper, that looks into large-scale immunization programs, recommends the widespread use of the varicella vaccine.⁴ So far, 44 countries have adopted either a partial or complete varicella vaccination schedule as part of their routine vaccination program. Of these countries, 29 have adopted a complete vaccination schedule by administering two doses of the varicella vaccine at an average age of 12 months for the first dose and 4–6 years old for the second dose⁵ (Table 1). No Asian country has adopted the vaccine as part of their routine vaccination program. The roadmap of varicella vaccine introduction year-wise and country are shown in Figure 1.

Figure 1. Road map of varicella vaccination with year of introduction vaccine with 1 or 2 dose in universal immunization program in various countries.

Table 1. Introduction of varicella vaccine in universal immunization program in different countries, vaccine strain, year of initiation and coverage of vaccine.

Country	Vaccine (Strain)	Year of initiation of Vaccination Program	Complete/Partial	Coverage
Antigua	Varicella (Oka, MAV)	2014	1 dose	–
Argentina	Varicella (Oka, MAV)	2015	1 dose	74%
Andorra	Varicella (Oka)	–	2 doses	–
Austria	Varicella (Oka)	2010	2 doses	–
Australia	Varicella, MMRV (Oka)	2005	1 dose	90%
Bahamas	Varicella (Oka, MAV)	2012	2 doses	–
Bahrain	Varicella	2015	2 doses	–
Barbados	Varicella (Oka, MAV)	2012	1 dose	–
Bermuda	Varicella (Oka, MAV)	2012	1 dose	–
Brazil	Varicella, MMRV (Oka, MAV)	2013, 2018	2 doses	>=80%
Canada	Varicella, MMRV (Oka)	2000–2007 (1 dose) 2011 (2 doses)	2 doses	93%
Cayman Islands	Varicella (Oka, MAV)	2000, 2009	2 doses	–
Colombia	Varicella (Oka, MAV)	2015, 2019	2 doses	–
Costa Rica	Varicella (Oka, MAV)	2007	1 dose	95%
Cyprus	Varicella (Oka)	2010	2 doses	–
Ecuador	Varicella (Oka, MAV)	2010	1 dose	–
Finland	Varicella, MMRV (Oka)	2017	2 doses	–
Germany	Varicella, MMRV (Oka)	2004, 2009	2 doses	75.3%
Greece	Varicella (Oka)	2006, 2009	2 doses	75%
Hungary	Varicella (Oka)	2019	2 doses	–
Hong Kong	Varicella, MMRV (Oka, MAV)	2014	2 doses	73%
Iceland	Varicella (Oka)	2020	2 doses	–
Israel	Varicella, MMRV (Oka)	2008	2 doses	–
Italy	Varicella, MMRV (Oka)	2017	2 doses	95%
Japan	Varicella (Oka)	2014	2 doses	40%
Kuwait	Varicella, MMRV	2017	2 doses	–
Latvia	Varicella (Oka)	2008, 2019	2 doses	–
Luxembourg	MMRV (Oka)	2009	2 doses	83.3%
New Zealand	Varicella (Oka)	2017	1 dose	–
Niue	Varicella	2017	1 dose	–
Oman	Varicella	2010	1 dose	–
Panama	Varicella (Oka, MAV)	2014, 2018	2 doses	–
Paraguay	Varicella (Oka, MAV)	2013	1 dose	–
Peru	Varicella (Oka, MAV)	2018	1 dose	–
Puerto Rico	Varicella (Oka, MAV)	1996, 2007	2 doses	–
Qatar	Varicella (Oka)	2007	2 doses	92%
Saudi Arabia	Varicella	2008	2 doses	–
South Korea	Varicella (Oka, MAV)	2005	1 dose	96.3%
Spain	Varicella (Oka)	2016	2 doses	86.1%
Taiwan	Varicella (Oka)	2004	1 dose	98.6%
Turkey	Varicella (Oka)	2013	1 dose	60.1%
UAE	Varicella	2012	2 doses	94%
USA	Varicella, MMRV (Oka)	1995, 2006	2 doses	90%
Uruguay	Varicella (Oka, MAV)	1994, 2014	2 doses	96%

Zoster vaccine

Zoster vaccine was licensed for use in 2006; there are two licensed HZ vaccines Zostavax and Shingrix. Zostavax (Oka strain) is a live attenuated vaccine that contains much higher virus titer with 19,400 pfu per dose of the vaccine.⁶ Shingrix is the recombinant subunit vaccine prepared using the VZV glycoprotein E and liposome-based AS01B adjuvant system, as it is a major target for VZV specific CD4⁺ T cell response.⁷ Zoster is known to occur following reactivation of VZV in about 30% of adults >50 years of age⁸ and it is also known to occur sometimes in those who receive varicella vaccine. The occurrence of varicella vaccine-induced zoster is now effectively managed with zoster vaccine.⁷

However, many countries have not adopted the varicella and zoster vaccines. There is a lack of perception for the need for varicella vaccine, merely because varicella is considered a self-limiting disease. The question that begs to be asked is, is varicella only a benign childhood disease? What about the impact of zoster on the elderly? In 1983, Thomas Weller expanded on the changing concepts of natural history of VZV and importance of a “NOT-SO-BENIGN” virus.⁹ He described unusual infections due to VZV in hematopoietic and reticuloendothelial cancers as well as the impact of congenital transmission of VZV on the fetus which consists of cicatricial scars, hypoplasia in one or more limbs and malformed digits.⁹ Central nervous system (CNS) damage manifests as convulsion, mental retardation, chorioretinitis and cataracts. There was also a strong association with the occurrence of Reye’s syndrome.⁹ Thus, the expansion of the spectrum of VZV disease can be traced back to 1983 and yet, the vaccine despite being available much earlier (1974) was first used only in 1989.

The further expanded spectrum of VZV diseases and the pathways of VZV latency

Varicella affects 3–16 per 1000 persons with considerable variations every year. Though, varicella is self-limiting, it can be associated with serious complications and death. In developed countries approximately 5 out of 1000 people are hospitalized and 2–3 per 100,000 deaths are reported. The incidence and hospitalization of varicella has dramatically reduced (>95%) in countries which have adopted varicella vaccination in their UIP.⁸ PHN seen in about 15% of cases is the most common complication of zoster. The incidence of zoster varies between 3 and 4 per 1000 persons. By the age of 85, >50% of the population have experienced at least one episode of VZV reactivation and zoster. The data on age specific incidence of zoster are limited in low- and middle-income countries. The precise incidence of zoster is difficult to quantify as all cases of zoster are not reported especially when it is mild.¹⁰ In Taiwan, varicella vaccine was introduced in 2004 (one dose); one-third of ischemic arteriopathies are associated with varicella in children, and up to 30% adults have a risk of stroke within 1 year of zoster.^8,11 A large population-based study conducted in China reported that the risk of stroke is higher (8.1%) in patients with zoster ophthalmicus.¹² The varicella vaccine was licensed for use in China in 1998 but is not part of NIP. The most common sites of VZV reactivation are the thoracic nerves and the ophthalmic division of the trigeminal nerve and about 0.25% of meningoencephalitis are due to zoster complications.¹⁰

VZV myelitis

Both varicella or zoster can lead to myelitis and VZV DNA may be found in the CSF of immunocompromised hosts. Myelopathy may be insidious and progressive, and sometimes fatal. Long-term usage of low-dose steroids may predispose to myelitis and encephalitis.¹³

VZV induced large and small vessel arteritis

Encephalitis or arteritis can occur in varicella or zoster in large and small vessels of the brain in both immunocompetent and immunocompromised hosts. Small vessels arteritis, which affects the CNS, most frequently occurs in the absence of rash. The presence of VZV DNA and/or anti-VZV IgG in CSF indicates acute or even recurrent myelopathy or encephalitis with or without rash.¹³

VZV vasculopathy

Following reactivation of VZV in trigeminal and autonomic ganglia, VZV can transaxonally travel to cerebral arteries. After deposition of the virus in the nerve ending, persistent inflammation can occur resulting in pathological vascular changes and stroke.¹⁴ There are increasing reports of VZV vasculopathy due to VZV reactivation and infection in cerebral vessels.^14–16 VZV vasculopathy can affect both small and large cerebral arteries; additionally, dural sinuses and extracranial vessels may also be affected.¹⁰

Other neurological manifestations of VZV

Neurological complications such as meningitis, meningoencephalitis, meningoradiculitis, cerebellitis, zoster ophthalmicus and facial nerve palsy can occur after zoster due to VZV reactivation, even in the absence of rash.¹⁷ The diagnosis of these conditions is confirmed by the detection of VZV DNA or anti-VZV IgG or both in CSF samples.^17,18 We have detected VZV DNA in meningitis, meningoencephalitis, encephalitis, Ramsay Hunt syndrome, zoster ophthalmicus and hemorrhagic stroke in both primary infection and reactivation.¹⁹

Gastrointestinal manifestations of VZV

Gastrointestinal (GI) manifestations of VZV and its latency in enteric nervous system (ENS) were recently established.^20,21 There have been several reports on VZV associated serious GI manifestations, worldwide. Reactivation of VZV in ENS can manifest as serious GI diseases such as inflammatory bowel disease, perforated gastric ulcers, acute colonic pseudo-obstruction,²² idiopathic gastroparesis, chronic intestinal idiopathic obstruction,^8,21 unexplained abdominal pain,²³ gastritis, gastric ulcers,²⁴ and ileocolic intussusception.²⁵ We have detected VZV DNA from participants with various GI manifestations including ulcerative colitis, Crohn’s disease cancer rectum, gastritis and gastric ulcers.¹⁹

Absence of rash and VZV – anomaly or new paradigm

There are extraordinary problems of inability for clinicians to accept that VZV can cause clinical disease in the absence of a vesicular lesion. This occurrence, though frequently documented in literature,^{8,14,17,21,22,26} is yet to find a place in textbooks. The paradigm of varicella as it is typically known to present, its usual signs and the complications of primary varicella, are viewed only as an expansion of normal science. VZV causing varicella and zoster is the paradigm. Mounting evidence generated by a group of scientific community has made way to create the problem of questioning this paradigm. Expansion of VZV disease, the different pathways that contribute to the expanded spectrum are causing a cluster of anomalies which the present paradigm cannot cope with and therefore suggests the need for a paradigm shift. VZV causing GI manifestations (colitis, gastritis) and vasculopathy are anomalies. These are significant anomalies which need to be examined further and not considered as a discrepancy that can be corrected over time.

During primary varicella infection VZV establishes latency in cranial nerve root (CNG), dorsal root (DRG) and sympathetic ganglia, via retrograde transport from sensory nerve endings. Alternatively, the T-cell viremia that occurs during primary infection may transport the VZV to neurons of DRG and CNG. There are no known direct neuronal pathways that exist between the skin through to the bowel.²² There are three proposed possible pathways of VZV to the ENS using guinea pig models; the first possible pathway is that VZV-infected neurons may potentially transmit VZV between somatic afferent and neighboring visceral afferent neurons, and via anterograde transport reach the ENS. The second proposed pathway is a putative viral conduit between the hybrid neurons that innervate both the epidermis and the viscera. The third possible pathway is via viremia, the virus is carried in infected T lymphocytes.²¹

It is difficult for the physician to reject the paradigm when faced with anomalies which have expanded to include the GIT. It is time to reject the existing paradigm of the typical varicella rash and substitute with another. Extraordinary research by several researchers have provided incremental data which is sufficient evidence for a shift in the paradigm.^{8,10,15,16,21,22}

Incidence of varicella and zoster in India

Cost benefit analysis and financial impact of varicella and zoster

Varicella infection in a tropical country like India occurs during adolescence rather than early childhood.^27,28 The financial impact, incidence, and burden of varicella disease for the general population in India is not well known.^29,30 In 2013, the Indian Armed Force started vaccinating their troops and calculated the cost-benefit of this scheme. The rate of hospitalization among the cadets and recruits due to varicella dropped from 24 per 1000 from pre-vaccination times (2003–2012) to 4.57 per 1000 post-vaccination.³¹ Although the cost of varicella vaccine was Rs. 1300 for two doses (price in 2013) may seem high, the cost of hospitalization and treatment of troops was higher reaching almost eight crores pre-vaccination. The cost of investigating the outbreaks and lost-man days were included in their calculations.³¹

A systematic literature review reported that HZ incidence was about 3–10 per 1000 person-years or 0.5% to 5.3% of admissions in the APAC regions.³² The economic burden of HZ and its complications however have not been extensively studied in Asian countries. A study based in Thailand found that each case of HZ averaged a total cost of USD 140.³³ Similarly in Singapore, the cost of treating a patient with PHN averaged USD 308.54.³⁴

In the APAC and SEA regions, several high-income countries looked into cost-benefit of introducing varicella vaccine into the UIP. Singapore and Taiwan both found that the bulk of the cost of disease was through indirect costs, lost work days for carers of affected children.^35,36 The pre-vaccination annual cost of varicella in Singapore and Taiwan were USD 19.08 million (1994–5) and USD 1.6 million (2002), respectively. Singapore calculated the cost-benefit ratio of introducing the varicella vaccine was 2.25:1 (approximately 2–3 USD saved compared to every 1 USD spent for the vaccine), this finding is further corroborated.^29,35

Is it varicella?

The disease burden of VZV is not known, as few cases of varicella are even reported. Most of the infected individuals do not visit the physician.^37,38

The clinical presentation of varicella and HZ is so characteristic that frequently no laboratory tests are done to look for the presence of the virus. Detection of VZV is essential for the diagnosis of VZV-induced diseases. Isolation of the virus using tissue culture was considered the gold standard for diagnosing VZV infection earlier, however it is time consuming, and facilities may not be available in all laboratories. Polymerase Chain Reaction (PCR) has replaced tissue culture and enables detection of VZV DNA; direct fluorescence assays are used to detect viral proteins. Chronic diseases such as vasculopathies, myelopathy and progressive outer retinal necrosis usually may not have any detectable VZV DNA, but demonstrable anti-VZV IgG will be present in CSF.³⁹ Amplifiable VZV DNA is usually present during the first week of illness and anti-VZV IgG antibodies by the second week of illness. The presence of anti-VZV IgG and the absence of VZV DNA is usually indicative of the chronic and protracted course of illness.³⁹ VZV specific antibodies can be detected in those with prior history of VZV infection and are also used to evaluate the immune status against VZV in the population.⁴⁰ Detection of anti-VZV IgG intrathecal antibody in CSF is considered a reliable diagnostic method for a diagnosis of VZV disease.⁴¹ Paired serum CSF anti-VZV IgG antibodies ratio with serum CSF albumin provides reliable evidence to rule out VZV in the absence of VZV DNA especially in protracted or prolonged illnesses.

Intrathecal production of VZV antibodies in varicella unvaccinated individuals with CNS disease

In a small exploratory study, we estimated the intrathecal anti-VZV IgG in CSF among 123 varicella unvaccinated participants (pediatric and adult) with evidence of CNS disease. The analysis was not used for therapeutic management. The mean value of anti-VZV IgG antibody in CSF in pediatric were 329.38 mIU/mL and in adults 1193.3 mIU/mL, with median of 30 and 432 mIU/mL respectively. Statistical analysis was performed between anti-VZV IgG levels between pediatrics and adults using GraphPad software v9.5.1. The p value was calculated using unpaired t-test (p = .003) was considered to be statistically significant.

We have compared the intrathecal IgG antibody levels among the pediatric and adult participants, adult participants had significantly higher titers of intrathecal antibodies compared to pediatric participants (Figure 2). In addition, we compared each of the neurological conditions among both adult and pediatric participants to determine whether there was any difference in the intrathecal antibody production (Figure 3). Irrespective of the neurological condition, all adults had significantly higher titers of antibodies; as all participants are unvaccinated, it is possible that in adults the higher antibody levels are due to reactivation (Figure 4(a)). No antibody titer was observed in 71% (39/55) of pediatric and 26% (18/68) of adult participants. Anti-VZV IgG titers among adult participants with acute neurological conditions such as meningitis, encephalitis and meningoencephalitis were compared with sub-acute or chronic conditions and statistically significant higher levels of intrathecal antibodies were documented among those with stroke (Figure 4(b)). The data shown here clearly indicate the need for investigation of neurological disease by estimating intrathecal VZV specific IgG antibodies in paired serum and CSF samples with paired CSF and serum albumin level for providing clinical evidence for VZV disease and initiating prompt treatment to settle the question of whether it is varicella or zoster.

Figure 2. Comparison of antibody titer between overall and anti-VZV antibody positive participants in pediatric and adult. Antibody titer was found to be statistically significant in adult participants (GraphPad 9.5.1).

Figure 3. Comparison of antibody titer between adult and pediatric in diverse neurological manifestations. Encephalitis/encephalopathy were found to be statistically significant (GraphPad 9.5.1).

Figure 4. (a) Represents diverse neurological manifestations in adult participants with antibody titer. (b) Comparison of stroke with acute neurological manifestations (encephalitis, meningoencephalitis, and meningitis) of VZV among adult participants (GraphPad 9.5.1).

Clinical condition abbreviation- E/EP– Encephalitis/Encephalopathy, ME – Meningoencephalitis, AFI – Acute febrile illness, I/AS – Irritability/altered sensorium, FS – Febrile seizure, SHT – benign intracranial hypertension, GP – Ganglionopathy.

Varicella and zoster vaccine dosing and efficacy

Varicella vaccine

Studies across Europe have looked at vaccine effectiveness (VE) and made recommendations regarding dosing intervals; VE were found to be 99.4% against severe disease after just one dose of the vaccine and 92% VE against all forms of the disease after two doses.^4,42,43 Despite having received two doses of the vaccine. However, 8% of children still had breakthrough mild infections after received two doses of vaccine.⁴² A two dose vaccination program, either as a combined vaccine with MMRV (Measles, Mumps, Rubella, Varicella vaccine) or as standalone varicella vaccine will prevent primary vaccine failure.⁴³ The dosing regimen has been shown to be most effective when the time interval between the two doses is short with a recommended time of 4 weeks,^4,42,43 currently implemented only in Austria.⁵

Zoster vaccine

The advisory committee on immunization practices (ACIP) recommended including of Zostavax for routine administration in adults >60 years age in 2006 to prevent complications of zoster⁷ with two doses at varying intervals.⁷ In 2017, Shingrix was approved by Food and Drug Administration and ACIP recommended for immunocompetent adults >50 years. The dosage of Shingrix vaccine consists of two doses, the interval between the 1^st and 2^nd dose should be between 2 and 6 months.⁴⁴ The efficacy of Zostavax is 51.3% and Shingrix is 97.2%.⁷

The way forward

The WHO position paper June 2014 recommends the varicella (pediatric) and zoster (>50 years immunocompetent adults) vaccines to reduce the risk of transmission and complications of varicella and zoster.⁴ Anne Gershon (2017) stated that the best way to control disease and spread of VZV is by vaccination against both varicella and zoster.³⁸ The cost–benefit analysis in the US showed that in the long term, benefits of administering the vaccine did outweigh the cost, because the number of sick days taken by children and their caretakers were reduced and the incidence of reactivation of the virus and the complications of HZ were also reduced.⁴⁵ However, the high cost of the vaccine (Indian Rupee 2200/- per dose) and the belief that primary infection with varicella provides lifelong immunity are major deterrents, to introduction of varicella vaccine in UIP.^45,46

The hesitancy for adopting the varicella vaccine is unclear. In India, Dr T Jacob John pediatrician, virologist, and vaccine expert believes that it is a matter of maintaining “status quo” (via personal communication and in Indian Pediatrics Images in Clinical Practice). He further adds that varicella is perceived to be not a killer disease. However, the number of deaths per year due to varicella, the number of children affected every year and the cost of roll out of varicella vaccine under the expanded program of immunization are not known. There is an urgent need for such data to be generated, whether one dose is sufficient, or two doses are required considering the wider age and spectrum of disease in India. Dr T Jacob John also adds that there is an urgent need to generate data on seroconversion rate against varicella among vaccinated children.⁴⁷

The success with vaccines against COVID-19 has clearly shown that India has the ability to manufacture large doses, which are cost-effective. Varicella vaccine is an optional vaccine, which is offered under IAP in the private sector and is used only by those who can afford it. We have previously documented (14% of CNS and 18% GI disease caused by VZV from different clinical samples).¹⁹ Earlier VZV reactivation was not a major concern because the life expectancy was 60–65 years. “WHO Decade of healthy ageing reports” suggest “that the number of older adults (>60 years) will increase by 34% from one billion in 2019 to 1.4 billion in 2030.”¹ Globally, the aging population is at risk of both varicella and zoster as a large majority of countries have not adopted the varicella and zoster vaccine. The aging population is also on the rise in India (life expectancy is currently at 70 years) and it is a step in the right direction that GSK has rolled out the HZ vaccine (Shingrix) on 24^th April 2023 in India, however the cost is high.

The pursuit of normal science will continue to provide evidence for the existing paradigm which the scientific community accepts, and which appears in textbooks. There are often incremental advances of normal science which is the basis for the knowledge gained. It is considered important to promote independent critical thinking in a scientific community yet a scientist pursuing innovative theory which may revolutionize science is met with criticism; this therefore leads the scientist being trained, to follow a paradigm that already exists. When X-rays were first discovered they were treated with shock, they actually “violated deeply entrenched expectations.” X-rays opened up a new field and changed age-old perceptions and practices.⁴⁸

The expanded spectrum of VZV disease that we have documented in the CNS (meningitis, meningoencephalitis, encephalitis, zoster ophthalmicus and hemorrhagic stroke) and in GIT (ulcerative colitis, Crohn’s disease, cancer rectum gastritis and gastric ulcers)¹⁹ and the mounting body of evidence in global literature, clearly make a case for use of both the varicella and zoster vaccines. The need for the vaccination and the problems associated with unvaccinated population requires better scrutiny by the Health and Government officials and a change in policy.

We have articulated the changing concepts of VZV disease, bringing in philosophy as advocated by Thomas Kuhn, as there is transition from normal science to revolutionary science. Science mainly advances by shifts in theory and not just by accumulation of knowledge. Normal science is based on research of past scientific achievements that a particular scientific community acknowledges as being the foundation for its future practice.⁴⁸ The expansion of the spectrum of VZV disease calls for immediate measure to adopt the varicella and zoster vaccines.

Author contributions

PS contributed to the conception, study design, data analysis, data interpretation, critical revision of intellectual content, reviewed and revised the final manuscript. The final approval of the version to be published and preparation of the paper. IA contributed to the data analysis, interpretation, and preparation of the manuscript and revised the manuscript. SNJ contributed to writing the section on the incidence, cost-economic data, and financial impact of varicella and zoster diseases in India and revised the manuscript RR, LNR and SV contributed to the interpretation of data and drafting of the manuscript.

Acknowledgments

We acknowledge the financial support provided by Scheme for Promotion of Academic and Research collaboration (SPARC) Graduate grant Program, Ministry of Human resource development, Government of India, IIT Kharagpur, India.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The work was supported by the Scheme for Promotion of Academic and Research Collaboration [SPARC/2018-2019/P851/SL].