Literature Review of Smallpox in India

Smallpox occurring naturally was eradiated worldwide by 1980, and the last case was identified in 1977.(1) Smallpox is a highly infectious disease which caused by two forms of the virus types – variola major which is most fatal with greater than 30% Case fatality rate (CFR) and Variola minor (also known as “alastrim”), which is less severe with CFR less than 1%.(2-4) The risk of death is higher among babies and around 30% overall after developing the disease in humans.(5, 6)

A third type of VARV found in late 20th Century which was common in West Africa had intermediate mortality with 1-10% CFR.(16) It transmitted between people and through exposure to contaminated substances or objects, and had no cure or proven treatment.(5, 7) The variola virus (VARV) is a large, linear DNA virus which is the causal agent of smallpox.(8, 9) Phylogenetics and phylogeography of VARV show the evolution of the virus since at least the 1700s and emergence of variants around the world, with the most severe naturally occurring strain, the India Strain, occurring in South Asia.(10)

Smallpox is potentially a bioterrorism agent despite being eradicated.(10, 11) The risk of re-emergence of VARV through  bioterrorism or accidental release is increased because of synthetic biology.(10) Smallpox reemergence through synthetic biology has been shown to be possible after the de novo synthesis of horsepox virus done by scientists in 2017.(13, 14) VARV is currently available in two world health organization (WHO) collaborating centers in the United States and the Russian Federation.(6, 15) Unauthorized experiments, accidental release of VARV and, potential bioterrorism are risks despite firm rules on VARV research.(6, 16) The impact of smallpox infection is generally among persons who are immunologically susceptible, with the highest mortality rate in people aged >45 years. (12)

Certain antiviral drugs and vaccines for smallpox might decrease the complications and mortality.(13) Several antiviral drugs such as Tecovirimat and Cidofovir may be useful in a public health emergency.(13) Smallpox vaccines were used successfully to eradicate smallpox.(13) Before contact with smallpox virus, if a person receives vaccine, it can prevent illness and if a person is exposed to virus, post-exposure vaccination is also effective. However vaccine is not protective if a person already has the smallpox rash.(13)

Smallpox in India

India was considered to have nearly 60% of smallpox in the world before the 1960s.(14) The particular smallpox strain of variola virus found in India was deadlier compared to the strains found in West Africa.(14) Considering this situation, the Indian government launched  the National Smallpox Eradication Program (NSEP) in 1962 with a goal of mass vaccination.(14) However, the mass vaccination program was difficult to implement and smallpox was increasing by 1967.(14) One of the reasons for the unsuccessful NSEP campaign was the method of delivery and quality of vaccine.(14) However, in partnership with the World Health Organization, India was able to get higher quality of vaccines and improved vaccine production in India.(14) Before 1969, the method of vaccination was using a single point needle and jet injector method, later changed to the multiple puncture approach using a bifurcated needle.(14) This could be used by trained lay people and did not require a doctor.

Another barrier for effective vaccination to large percentage of people was the high birth rates in India each year and difficulty tracking unregistered births, which constrained the mass vaccination strategy.(14) Therefore, a new strategy called “surveillance-containment searching” (ring vaccination) was implemented to improve the vaccination attempt.(14) With this new strategy, health care workers and trained village workers were appointed to search 100 million houses in India through a six day visit each month and this was conducted by Indian officials, international advisors, field workers and district health personnel who did searches in houses of 2,641 cities and 575,721 villages.(15) The staff recruited by the WHO team in India were trained to determine situations and identify smallpox outbreaks, track infection sources and start containment actions at each inspection stages.(15)

Another unusual step was giving a financial reward for reporting smallpox, which became very effective and increased the smallpox cases reporting by the community to 11% in 1975 as compared to only 2.6% reporting achieved in 1973.(15) This showed word of mouth reporting remained the most influential means of detecting new smallpox cases.(15) The last case of smallpox was observed in May 1975 in India.(15) Active surveillance for new smallpox cases continued for the next two years.(15) New smallpox cases were searched for in more than half million villages and 260 towns areas of India between March to November in 1976.(15) The international commission visited India in April 1977 for the evaluation of smallpox eradication in the country, and finally certified India as free from smallpox.(15) Two years later, the Global commission for the evaluation of smallpox announced that smallpox is now eradicated from the world completely.(15)

 

Population and demographics of India:

India’s population in 2016 was about 1.324 billion, and India is the second highest populated county in world behind china.(16) It is estimated to be highest population by 2024 surpassing China.(17) According to 2016 estimation, the growth rate of population is 1.19% and has 96^th position in world rank of population growth rate.(18, 19) More than 50% of the population in India are under 25 years of age and more than 65% population under 35 years of age.(20) From estimation, it is considered, India’s average age would be 29 years in 2020.(20) In 2016, India has sex ratio of 944 females for 1000 males(21) and population density is 382 people per sq.km from 2011 evaluation.(19)

From 2016 evaluation, birth rate was 19.3 births per 1000 population and death rate was 7.3 per 1000 population.(19) The overall life expectancy was 68.89 years from 2009 estimation where male has 67.46 years and female has 72.61 years. The fertility rate is 2.2 children per woman(22) and mortality rate of infants is 41 per 1000 live births according to 2016 estimation.(23) The sex ratio at birth is 1.1 male per female(2013 estimation); under 15, 1.1 male per female; between 15-65 years, 1.06 males per female; over 65, 0.90 males per female(2009 estimation)(19)

Health systems in India:

Public health-care infrastructure :

The health systems in India consist of both public and private health service providers.(24) Over 80% of healthcare is provided by private health services providers and urban areas support both secondary and tertiary level of health services.(25) In rural areas of India, the infrastructure of public health system has been improved as a 3 tier process considering the standard population of India.(24)

The Scheduled castes (SCs)in India is getting 100% central assistance since April 2002 from the Ministry of Health & Family Welfare in form of drugs, equipment, rent, emergency expenses and  salaries.(25)

Conclusion:

The current focus of India is  on maternal and child health and supporting complete care to both child and mother. However, it requires attention to planning and policies such as increasing capacity of the human resources, improving further distribution of budget towards newborn care support; enhancement of quality and quantity of newborn care in the country.(25)

Healthcare in India:

Public healthcare:

In India all government hospitals provide free healthcare, but less than 20% of people receive care in the public sector.(26) Those people below the poverty line receive free healthcare from public health sectors, but access to care is low in rural areas.(27) Total outpatient care   is 18% and inpatient care is 44% in public health sector compared to private healthcare sector,(28, 29) mostly utilized by lower class individuals, females and elderly people as compared to middle and upper class people who mostly prefers private health care.(30)

Moreover, the dependency of people on private and public health sectors differ considerably in different states. The more inclination of individuals towards the private sector compared to public is because of poor quality of healthcare in the public health sector and more than 57% of households consider the reason of choosing private care sectors.(31)

Since most rural areas are serviced by the public health sector, the professional healthcare providers show reluctance to work in rural areas which leads to low quality health care in rural areas. As a result, most public healthcare sectors in rural areas depend on inexperienced and junior health workers. Long distance of public health facilities from villages and unsuitable operation hours are other major barriers to care.(31)

After 2014, the India government revealed plans for countrywide universal health care system called the National Health Assurance Mission which would support free drugs, health insurances, diagnosis treatments for all citizens.(32) However, in 2015, this universal health system plan was delayed due to lack of budget.(33) The Indian government declared another scheme in April 2018, called the Aayushman Bharat scheme which targets to cover up to half million to 100 million unprotected families (nearly 500 million individuals) which would cost $1.7 billion every year and delivery would be through private health sectors.(34)

Private healthcare:

The private health sector is considered to contain most health capacity in the country i.e. 58% of the hospitals in India and 29% of beds, and the percentage of doctors in private health care is 81.(28) Private hospitals are the primary healthcare source according to a National Family Health Survey-3; In urban areas 70% of households and in rural areas 63% of households prefers private healthcare according to this survey.(31) According to IMS Institute for Healthcare Informatics study in 2013, in more than 14,000 households of 12 states, the study showed, in urban and rural areas of India, there was a steady increase in utilization of private healthcare for Inpatient and outpatient services over a period of last 25 years.(35) From 2012 study on healthcare quality in health sectors by Sanjay Basu et al. showed that the private healthcare providers spend more longer time with the patients and do physical exam as compared to those public health providers.(36) Another study indicated that the poor people in India spends over 35% for health expenditure in private healthcare.(37)

Since there is no regulatory authority to inspect the misconducts in private health sectors, they provide high quality operations and treatment at unaccommodating costs.(38) According to a report, 40% of the practitioners of Rajasthan did not have a medical degree and 20% of staff have not finished their secondary education.(39)

Healthcare access:

Although, India has more than 1.4 million doctors, it failed to achieve the Millennium Development Goals associated with health.(28, 40) This failure is due to lack of universal provision of healthcare, utilization and accomplishment.(40) Inequalities for access to healthcare is due to divergent supply of health services, resources, and power.(39) Another barrier is variation in funding healthcare; inavailability of adequate infrastructure in high dense poor people areas; and long distance from health care sectors. People with highest need of healthcare are deprived of medical facilities.(39, 40)

Public health surveillance and response infrastructure:

1) National Surveillance Programme for Communicable Diseases:

In 1997-98, National Surveillance Programme for Communicable Diseases(NSPCD) launched by centre in five districts and then extended up to 101 districts of all 28 states and 7 Union territories in the country over the years.(41) Through this program weekly outbreak reports of epidemic prone diseases were sent to the centre from the districts.(41, 42) This programme main aims were, to build early warning system so as to establish timely response for outbreak prevention and control.(41, 42) This program covers surveillance of most of the epidemic prone communicable diseases, pathogens with bioterrorism potential, drug resistant pathogens.(41, 42) The goals of NSPCD were early outbreak detection and establishment of containment measures, morbidity and mortality reduction etc.(41, 42)

2) Integrated Disease Surveillance Project:

Under the Ministry of Health and Family Affairs in India, the Integrated Disease Surveillance Program (IDSP) initiated and aided by world bank.(43) The IDSP program continued from 2012- 2017 under national health mission.(44) For the quick response of outbreaks and detection of infection diseases through surveillance is the main aim of this program.(45) The IDSP scheme attempts to build up district, state surveillance unit in every state to collect and inspect the data, and centre disease surveillance system unit.(45) The Central surveillance unit(CSU) was set up by the world bank funds at National Centre for Disease Control (NCDC) and in Uttarakhand, Rajasthan, Tamil Nadu, Karnataka, Andhra Pradesh, Punjab, Maharashtra, Gujarat, and West Bengal and the domestic budget funded the rest 26 states or union territories.(45)

In July 2008, under IDSP, media scanning and verification cell(MSVC) was included for enhancing event-based surveillance and detecting uncommon health reports received from media.(45) The main objective of the program was to set up decentralized disease surveillance system for effective and timely action on public health events and for enhancing disease surveillance efficiency.(45)

Whenever disease trends rise in any region, these data are collected under IDSP on weekly basis from Monday to Sunday, which is examined by rapid response teams.(46) As a result, the weekly surveillance reports were reported from 90% districts in March 2014.(46)

3) National Health Mission:

The National Rural Health Mission(NRHM) launched on 5^th April 2005 to address rural areas health needs who had weak public health systems and implemented in 18 states.(47, 48) In 2013, government of India launched National Health Mission (NHM) including both National Rural Health Mission(NRHM) and Nation Urban Health Mission and in March 2018, the mission then extended to continue till 2020.(48, 49) The mission aims to provide community acquired, completely functional, decentralized health supply system with connection between outside sectors.(48) The NRHM program will be stronger as per the 12th plan document of planning commission under National Health Mission considering the upscaling of NRHM to cover noncommunicable diseases.(48) The initiatives taken under National Health Mission (NHM) are Janani Suraksha Yojana (JSY), National Mobile Medical Units (NMMUs), National Mobile Medical Units (NMMUs), National Ambulance Services, Janani Shishu Suraksha Karyakram (JSSK), Rashtriya Bal Swasthya Karyakram (RBSK), Mother and Child Health Wings (MCH Wings), Free Drugs and Free Diagnostic Service, District Hospital and Knowledge Center (DHKC), National Iron+ Initiative, Trible TB Eradication Project etc.(48, 50)

Vaccination policy and history of Smallpox vaccine:

Locally and worldwide, India is among the top buyers and producers of vaccines ad aimed at depending on its own vaccine production and technologies with current vaccines in India evaluated approximately US$260 million.(51, 52) The first policy for childhood vaccination took three decades to effective after independence and in 1978, six childhood vaccines implemented in India i.e. Bacillus Calmette-Guerin, TT, DPT, DT, polio, and typhoid.(51) In late 1990s, the shortage of vaccines started due to implementation of more sophisticated, expensive and new vaccines which led to discontinue production of low cost, traditional vaccines in developing countries like India.(51) As a result, 10 manufacturing companies out of 14 terminated traditional vaccine production between 1998 to 2001.(51)

These introductions of new and more expensive vaccines made a rapid growth of about 8%-10% per year in vaccine market of India.(51) Moreover, the government also pressurized from industry to include new vaccines in Universal Immunization Programme(UIP).(53, 54) The competition of cost and supply by the companies determine the decision of government on vaccination.(53) These vaccines are now adopted by consumers so fast due to many campaigns promoting new vaccines and support from private medical practitioners.(51) In 1802, smallpox vaccine arrived in India four years after the publication of Edward Jenner’s work in 1978 named “An enquiry into the causes and effects of Variolae Vaccinae”.(55-58) The immediate and wider acceptance of smallpox vaccination was due major differences of vaccine over variolation.(55, 59-61)

Vaccination in the period 1802-1899

In May 1802, India got its first dose of lymph smallpox vaccine and on June 14, a child from Bombay received first smallpox vaccine.  Then, this vaccine from Bombay sent to Madras, Pune, Surat, Hyderabad.(55, 58) In the 2^nd half of nineteenth century, the concept of ‘paid vaccinators’ system started due low coverage in rural areas.(62-68) In 1892, smallpox vaccination act passed to supply high smallpox vaccine coverage and decrease the epidemics.(55) Before 1850, Great Britain was exporting smallpox vaccine to India, however there was transport challenges increased and the shortage of smallpox vaccine happened due to the rise in demand of vaccines in upcoming years.(55) While, the high vaccine supply in late19^th century led the focus of research on efficient techniques of vaccine storage to make certain vaccine material delivery to rural areas and the areas which hard to access.(55)

Vaccination in the period 1900-1947

In the beginning of 20^th century, the vaccination coverage decreased due to the Government of India Act of 1919 and the World war II which led to large number of cases of smallpox in 1944-1945.(55) Surprisingly, after the end of world war II, the smallpox cases went down due to more focus on smallpox vaccination.(55, 58, 59, 62, 63, 67) In the beginning of 20^th century (1900-1947), many research institutes manufacturing smallpox vaccine as lymph. Since 1890, the vaccines were being manufactured in Shillong and some other places.(67) In 1904-1905, Smallpox vaccines was produced in Central research institute situated in Kasauli, Himachal Pradesh and in 1907, the Pasteur Institute of southern India, Coonoor was manufacturing vaccines.(69-73)  Smallpox vaccine lymph manufacturing institute were set up in every states by government of India. The manufacturing institutes became the centre for production and research on high quality vaccine, serum and preservative techniques for long period of storage of vaccine materials.(55, 67)  The number of smallpox reporting cases was maximum at time of independence in India.(55)

In 1958, to eradicate smallpox, the World Health Assembly (WHA) passed a decision in the event after which in 1962, National Smallpox Eradication Programme (NSEP) started in India with the goal of vaccinating whole population successfully in upcoming three years.(55, 59, 64) The program had ‘attach phase’ to cover 80% population and also ‘maintenance phase’ included vaccination to infants, all newborns, and 5yr, 10yr, 15yr children.(55) After implementation for five years, this strategy has low coverage and with reporting of outbreaks still obtained due to reason of difficult to access population and the same persons many times were getting vaccinated.(55, 64-66)

Vaccination in the period(1947-1977)

During independence, India was self-dependent  on smallpox vaccine production. In 1948, laboratory of BCG vaccine organized in Guindy with goal to produce sufficient vaccines as per the requirements in India.(55) Also, the vaccine production units were set up in private sectors.(55) In 1971, there were 19 public sector vaccine production centres and  12 units in private sectors.(55) In 1978, India launched National Immunization programme known as Expanded Programme of Immunization (EPI) after India became free from smallpox in 1978 and the program introduced OPV, BCG, DPT, typhoid and paratyphoid vaccine.(71, 72) The main goal of the EPI was to vaccinate at least 80% of infants and provided through big hospitals which largely covering the urban areas and therefore, gave rise to low coverage.(55, 74)

After the eradication of smallpox in India, the vaccine production for smallpox stopped in 1979.

 

Conclusions:

On one hand, India enjoyed the benefits of prior successes in R&D of vaccines and  local vaccine production in the public sector, where as in other hand, India is not able to fill the increasing gap in demand as well as delivery of UIP vaccines.(75) In India the UIP vaccines availability from private sector is decreasing and it is in favor of new and more expensive vaccines whose need of public health has not been exactly instituted in India with reasonable cost benefit data and epidemiological data.(53, 76) To fulfill the vaccination requirements within the budget, India should develop its own vaccination strategies.(51)

 

Research Plan

Aim and objective:

The main aim of my thesis is to study the epidemic impact of smallpox in India with and without interventions.

Research plan:

In a comprehensive manner, the research findings would address the number of people would get infected in India in the event of smallpox re-emergence with different attack rates; the most affected age groups; the rate of infection using ring vaccination strategy; the impact of vaccination on rate of smallpox infections, recovered and death rates. We aim to test the ring vaccination strategy response to control the outbreak.

Methods:

I will modify an existing SEIR model for smallpox for India.(77) My research will include:

1. Revising the model for the Indian population structure. I will use India’s population and health care workers in 2015 which is collected from the data of United Nations, Department of Economic and Social Affairs, Population Division (2017),  World Population Prospects, the 2017 Revision.(78) The India’s population by 5-year age group up through ages 80–84 years also obtained from the same sources of United Nation and summed up the eldest  ( >84 years of age) into a single group (85+).
2. Developing a contact matrix for India and incorporating this into the model.

In the SIER model, I will use the both physical and nonphysical age-specific contact rates of Italy from the European mixing patterns study,(79) which has higher contact rates. I will research family structure and size, population density and other parameters in India compared to Italy and apply a correction factor to develop a contact matrix for India.

 

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