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May 3, 2015

3rd day update: 9th International Conference on Typhoid and Invasive NTS disease - Bali, Indonesia

The day started with a symposium on past experience from typhoid vaccine implementation: translating global policy to country use. This was moderated by Kim Mulholland, LSTM, UK. The talk started with Nepal Vi – ps introduction in Nepal. Dr. Pradhan urged international community to assist GON to introduce typhoid vaccine in its national EPI program. The second talk was given by Leon Ochai on vaccine introduction in Pakistan. There was also mention of DOMI program and its relation to assess vaccine effectiveness in the real public health situation with >60 % effectiveness > 5 years of age. It was introduced as school based vaccination. I could see that the coverage was average around 60 %. It was related with trust to the system, the reason for low coverage.
Where do we stand?

  •  Burden of TF – high along with MDR / age of infection as low as 6 months
  • Vaccine use: TF vaccination is efficacious and feasible / capability for vaccinating school children
  • National financial resources limited
  • Global agency financing will facilitate the vax introduction and help in controlling this disease
  • Sri Lankan experience: Jaffna (IDP camps) has the highest incidence of TF followed by Colombo (with highest population) in SL. Vaccine being given to outbreak situation / pilgrims / food handlers / close contact of patients / where water sanitation (poor)/health professional / armed forces / children with frequent of diarrhea. However, there is high literacy / improvement in WSH. There is also environmental surveillance.
  • surveillance – sentinel + lab surveillance
  •  Antibiotic monitoring
  •  Immunization in High risk areas

Conclusion: Government is willing to vaccinate and GAVI is also willing to finance this initiative. We should not hesitate to move forward. Also, we need environmental sampling + improvement in WASH

Integration of TF vaccine in NI Schedule: opportunities and challenges from industry (Bharat Biotech – India). There is higher disease burden in urban so urgent need for its control. (Ochiai + Florian’s paper) Typbar – tcv (6 months and above / single dose / IM – what r the key consideration (WHO ECBS guideline on Typhoid vaccine use)

  • Primary above 6 months / Single dose / at least 6 months of gap for boost / or school based booster
  • Current guidance available NIH efficacy studies
  • New Vaccine Introduction from WHO perspective (Principle, Practices and Realities) -
  • Moving fast

o   Measles vaccination
o   HiB introduction
o   Rubella vaccination
·                     Slow to medium progress
o   JE vaccine – regional vaccine
o   Pneumococccal
o   Rota Vaccine
o   HPV vaccination – cervical cancer

Various scenarios
·         Scenario A - ??
·         Scenario B – low income countries – GAVI funded / sustainability?
·         Scenario C – Gray area / prioritization

Key point to consider – decision making process

·         Burden of disease – various factors (eg incidence / mortality / DALY)
o   Accuracy of the burden studies (syndrome sx may overestimate)
·         Factoring in vaccine efficacy and its effectiveness – looks into overall effectiveness of the vaccine
o   Herd effect / impact
Key message
·         Vaccine effectiveness > efficacy
·         Vaccine factors – age / booster / dosing …..
·         Alternative ways to control also available but for example measles – vaccination is the only option
·         Cost – opportunity cost / cost benefit
·         its priority in government
·         Return on investment
·         Health budget
·         Global agenda (political / global initiative)
Question and answer session
·         what is the vaccine efficacy among 2 to 5 years of age
·         Some voice against using the word ‘alternative” in relation to vaccination e.g. HPV vaccination
·         Typhoid vaccination – John Crump interested with vaccination against frequent in acute diarrheal illness.
·         Breiman – 2 to 5 years of age  vaccine efficacy (factors like fear / poor acceptance might have influenced the low efficacy rate among 2 to 5 years)
·         The effect of taking consent may have an effect on low coverage
·         Dr. Bhutta gave a clear and succinct explanation of why low coverage in Pakistan.
Next symposium is on development of vaccines against typhoid, paratyphoid and NTS. This is the key area where I have an interest. This is moderated by Adwoa Bentsi Enchilli, WHO, Geneva, Switzerland
Ghananian proverb – lesson to be learnt from past
Typbar – TCV (Bharat Biotech, India)
·         Safety and immunogenicity in healthy infants, children and adults in endemic areas
·         control – Typbar (Vi – PS)
·         dose = 0.5 ml / cold chain needed
·         anti Vi igG 6 wks post vaccination – 1 endpoint
·         Safety across 6 months – 45 years
·         Results:
o   safe in all age group
o   Immunogenic (high IgG response) also in < 2 years
o   Persistent in immune response and also memory response
o   antibody avidity is important for qualitative assessment
o   Open label / controlled trial  - TypBar TCV / Typbar
§  Conclusion – safe / immunogenic / immune response persistent < 2 years / booster needed
§  Measles interference study underway
o   My question – Bharat Biotech is way ahead with their conjugate vaccine, how we are going to deal with it as we are working with Vi – DT vaccine

Vi - DT vaccine development – Bio Farma
§  our desire to move from medium > high priority in WHO list of vaccine
§  Target Product Profile (TPP)
§  Process development  / GMP process – master seed and working seed
§  Process flow (Vi Polysachharide)
§  ELISA / NMR /HPAEC method
§  WHO TRS 987 – requirement
§  Vi DT conjugation Process
o   Carrier protein prep
o   Vi PS preparation
o   Conjugation
o   Diafiltration
§  HPLC profile
§  Nonclinical immunogenicity studies (who guideline)
Vi CRM 197
o   CRN
o   Conjugation kinetics as a process map
o   Bulk conjugate vs. Formulated Bulk
o   Study plan – mice study
Live oral vaccine – M01ZH09 (from parent Ty21a with some changes) Ref: Waddington et al, J Infect 2013
o   Vax efficacy / correlates of protection
o   Vaccine efficacy – study design
o   blinded arm (Placebo vs M01ZH09)
o   Open arm (Ty21a)
o   LPS as surrogate of efficacy
o   Then challenge with TF bacteria / diagnosis after challenge (temperature or Blood C/S)
o   Dose escalation study
o   LPS vs. Flagellen vs. Vi
Bivalent Core and O PS (COPS) – flaggelin conjugate vaccine against iNTS and typhimurim infections
o   key - phase 1 flaggellin subunit serves as the carrier protein – target for immune response
Interesting discussion – I guess on emerging considerations for iNTS disease prevention moderated by John Crump, University of Otago, New Zealand
Typhoid conjugate vaccines for public use: overcoming barriers moderated by Zulfiqar Bhutta, University of Toronto, Canada
TF vaccine for public health use: overcoming barriers: moderated by Zulfiqar Bhhutta
o   Current WHO position of TF (2008) – recognition as serious health problem/significant public health burden/local epidemiology/high risk population must be the target/ there are also inadequate data on conjugate vaccine (t cell response / ? young age group)
§  national epidemiological data – rapid assessment tool to map the disease epidemiology (better describe the local epidemiology)
§  Lack of validated assay
o   GAVI – Vaccine Investment Strategy (VIS)
o   2008 HPV/JE / rubella, typhoid conjugate
o   2011 interest in typhoid conjugate
§  WHO PQ and recommendation
§  GAVI program window decision
§  Program implementation
§  Vaccine evaluation
·         vaccination scenarios
·         Demand forecast
·         Develop impact estimates
·         Develop cost estimates
·         Assess other disease / vaccine feature

o   International Vaccine Institute (IVI) -  landscape of what IVI is doing in Vi DT vaccine development
o   Gates Foundation - Stringent and focus / fulcrum of knowledge, innovation and technology / accelerate the product development program (PDP) / focus and ambitious / using the vaccine so we can eliminate it (nationally / regionally)/ integrate vaccine and WSH or other strategies necessary / engagement – innovation so we can address 
o   GAVI process / SAGE – uncertainties re: disease burden – magnitudes / distribution, target age group, strategy utilizing
o   micro planning of deployment – generate evidence / advocacy / once WHO pq we can use it also convince the investors / also generate demand – in direct communication with policy makers so we convince them, prepare ground for deployment of vaccine, guidance of regulatory authorities at country level
o   GAVI – key is evidence / disease burden data – matrix of investment
o   Immunization strategy need to be carved out and political will is also important / political commitment is always need – local champions and translating local data and connecting with policy groups through advocacy and communication
o   Need for efficacy data
o   Lack for good diagnostics so this could help surveillance
o   Transfer of plasmid is on threat??
o   Nepal could advocate strongly in WHA through executive body – how can we move forward???? / Position should focus on implementation part.
o   Global Typhoid Initiative – need

o   description, discovery, development, delivery

2nd day update: 9th International Conference on Typhoid and Invasive NTS disease - Bali, Indonesia

AMR symposium
·         key message is that MDR is an issue with treatment of TF with antibiotic
·         Need for close cooperation to address this problem between clinician and laboratory experts
Genomics and host susceptibility to enteric fever and NTS disease
·         HLA and resistance to enteric fever
o   this is beyond my understanding
o   Key messages:
§  HLA –DRB1+0405 major contributor to resistance
§  May affect antigen presentation
§  T cell response
§  Key individuals in PAHS Salmonella study – Well Come Trust
·         Buddha Basnyat
·         Samir Koirala
·         Sabina Dongol
·         Amit Aryal
·         Abhilasha Karki
Immunity to invasive S infections: lessons from animal models and man
·         System infection progress in distinct phases
o   Innate response
o   Adaptive response (inflammation)
o   T cell dependent acquired immunity
·         “Like a castle cards” – interesting analogy
·         Dynamics of the “in vivo” infection process, immunity and vaccination (thru molecularly tagged or fluorescent)
·         Dispersive infections with intracellular and extracellular phases (analogy - catch me if you can!!)
·         Lessons from Human - vaccines
o   How can we expect the infection with external intervention?
o   Optimize antibody response: isotypes and effector functions
o   Primed cellular response
o   Ab + Cell mediated immunity
o   Epidemiological risk factor vs. susceptibility to disease ( innate immunity and adaptive immunity)
·         Novel insights in host response to understand pathogenesis
o   Typhoid challenge model
o   Waddington et al., CID 2014
o   Cytokines – early response (disappears after 12 hrs)
o   Gene expression after challenge
§  Interferon
o   Cytokines – post response
Typhoid toxin (geno toxin) - Song et al, Nature (2013) absent in non typhoidal Salmonellae
  • Fundamental questions
  • Cytolethal distending toxin + Pertusis toxin

o   Why it causes typhoid fever?
o   Why it only cause disease in humans?
o   a novel toxin and a novel pathway for exotoxin delivery by an intracellular pathogen
o   Salmonella cultured does not produce it??
o   S ty[phi does not survive ……intracellular macrophage
o   Rab 32 / 38 dependent pathway in macrophase  - mechanism of restriction in mice
o   Typhoid organism must have adapted well in humans thru certain sialic acids / glycans
o   Toxin can not affect chimpanzees
o   Deng et al, Cell (in press)

May 2, 2015

First day update - 9th International Conference on Typhoid and Invasive NTS disease - Bali, Indonesia

The first day of the 9th International Conference on Typhpoid and Invasive NTS disease was very interactive. This conference has provided us with a tremendous learning opportunity the amount of work that has been put into understanding Typhoid fever and invasive non typhoid salmonesis.
The day stated with Florian’s (from IVI) talk that provided us the update that include challenges on TSAP project in Sub Saharan Countries. This was followed by Kashimira Date’s talk which also updated on Surveillance of Enteric Fever in Asia (SEFA) project (including in Nepal). I had chance to meet those involved in this project. CDC / GTA along with GON.

Namrata Prasad and  Aaron Jenkins talked on Fiji Typhoid fever study which included case control (CC) study in Fiji, 2014 and another study whose objective was to carve out determinants of typhoid fever in Fiji (multidisciplinary study). The interesting part was the assay work on Soil samples (from houses of cases) and also there was mention of localized behavior / household environments
  • Urban vs. Rural  (what is the key criteria that differentiate U vs. R)
  •  Geospatial analysis – water supply along with sanitation
  •  Soil sample - how long do the organism last in the soil? (7 to 10 days??)
  • Hand washing – behavior vs. education vs. introduction of bias??
  • Reported vs. observed hand washing practices
  • Does those sites selected (Africa / Asia) really represents the true picture?
  •  Larger geographic sites – could be a greater effort
  • Rapid assessment: cases – from all hospitals / age wise breakdown (? physician’s opinion/survey of sanitation led by governments/spotty / patchy distribution of typhoid fever in Africa (this is what they observed despite good lab facilities)
  • Rapid assessment tool (RAT) - real challenges??
  • Paratyphi
  • 20 % of total Africa population
  • Drug resistance – Ciprofloxacin
  • Vaccine acceptability??

The second session started with a presentation from University of Jakarta on clinical and demographic characteristics of TF in Indonesia. The below are some of the key messages:
  • 64 % TF in 3 – 19 yrs (Indonesia)
  • 3.1 to 10.4% - mortality in hospitalized patients
  • 2nd important infectious diseases
  • Less than 20 liter per day – cut off point

The second and third talks were on mathematical modeling. The first was more focused on the potential consequence of the H58 haplotype of Salmonella Typhii. The following are key messages:
  • Patan Hospital study – KTM Nepal compared to Malawi study
  •  Emergence of H58 haplotype
  • Why is typhoid incidence increasing in Malawi?
  • Bowles CC et al (in prep) – Patan hospital study
  • Infectiousness/ R0
  • usually 4  weeks shedding of bacteria
  • Transmission rate
  • Better diagnostics needed
  • Chronic carrier in the community   
  • ? natural immunity and its role
  •  Influx of susceptible migrant male workers form low incidence rural regions in the country

o   Increasing pop density
o   Cross immunity

The third study was from LSTM / University of Liverpool on modeling in relation to malaria / hiv / malnutrition. While the fourth talk was on Evaluation of a rapid real time molecular assay (S. typhi, paratyphi and S. spp.) from Foundation Merieux, France. The final talk was by Dr. Quadri on Typhoid in Bangladesh: from infection to protection. Some of the key points were on immune response in children (Ty21a) oral route and also about IgA / ALS
  • Widal tests
  • Blood c/s

This was also a panel discussion to discuss challenges and approaches in measuring typhoid fever disease burden. The following points were key point discussed:
  •  Research vs. public health mode – what is more important?
  • Generalibility  of what so far we have scientific data
  • Rapid Assessment approach – e.g. used for Pneumo vaccine introduction ( may be based on serology)
  •  It seems – typhoid organism does not survive much in environment!!
  • Shousun Szu – vaccination is important for protection
  • Government’s role and opinion is important
  • Importance of severity study is more study as government policy makers interests in mortality data
  • Policy and global / local investment – data / data / data that represent across geography and age group
  • Partnership across various groups / researchers
  • HiB rat
  • WHO: visibility of the disease – evidence / measures / advocacy

The discussion was followed by symposium on water, Sanitation and hygiene (WASH) interventions for enteric fever control. The key points that were discussed as follows:
  • WASH interventions for enteric fever control ( a ppt. by Standard University)
  • Linking typhoid transmission to the water distribution with water system
  •  main factors for transmission
  •  live change and your risk
  • specific haplotypes circulation and how
  • GPS mapping
  • “Water quality in KTM is poor
  • Typhoid fever, cholera and hepatitis
  • Municipality water supply
  • Surveillance will be the way we will control infectious disease / sort our antimicrobial resistance (AMR) 
  • Why is the H58 lineage so successful? 
  • S. Typhi in the Pacific region are generally island specifics
  • Is this an opportunity for an eradication program?
  • Bring a solution in front of Politician’s nose and hammer it

Open talk on cholera, Dr. Sack's question and Nepal - Part 2 of 6 parts series

This year also, we are hearing  reports of cholera outbreaks in Sub Saharan countries like Malawi, Mozambique and so on. I have been following these outbreaks closely through promedmail updates, however the only limitation that I personally feel is that I do not know first hand information of its seriousness in the local community. I love to hear those who have been engaged in its control and prevention especially those closely involved in Malawi vaccination. Reason after all, "seeing is believing" and this is true !! In this light, once I read an experience of a Nepali young doctor - Mr. Partha Bhurtel, who volunteered and served to care people in remote villages of Jajarkot during the tragedy called Jajarkot as a result of cholera outbreak that took lives of many unfortunates. When I read his real field experience as an opinion piece. Oh, it was heart touching. Once I read it - I have begun to question what is my purpose as a health professional? Nonetheless, we have to be objective and do our best from our part what we can do. Sometime we can do nothing but just pray. That is what it would be reasonable. You can read opinion piece : Dissecting the cholera outbreak in western Nepal  I take this story as a real public health endeavor at personal level very passionate. 

While getting shocked with real public health crisis of Jajarkot, I had a chance to read a recent blog post by Dr. David Sack in STOP CHOLERA JHU website: He ask a very important question: "How to handle the mismatch between actual needs and the practical use of current tools for cholera surveillance, prevention, and control?" Dr. Sack is asking a very practical question, which is the same question I also have in my mind. This is important when we go back in our memory line of Haiti and Jajarkot outbreaks. Well I have to be honest, I do not have a concrete answer but let us exercise our mind by asking: What is the real issue here? 

This real issue can be summarized in one question after it is several questions in long procession," Have we been successful in addressing this deadly disease called cholera in Africa, Asia and some Pacific islands especially during disasters?" Well I am not the right person to answer this "loaded" and "heavy" question, instead I would like to put forward opinions so let me link this question in a way that would make sense to Earthquake in Nepal. We faced an sudden and unexpected natural calamity of such magnitude that we are struggling with it. We are so far being tested so far of what nature Nepali people are built with be it physical and of course - social and moral integrity at this time of such despair. Anyway, we are fortunate that we are coping and dealing with the situation as it comes. However, it is one bitter truth that our disaster preparedness should be robust and now onward we have to hard work on it. This means this preparation must spreads across all faculties. People have started to question the government's very core of functioning. This is high time we act quick and adapt to the situation. Sure, the political landscape has to change. You may also say, we are talking about cholera and what in the world, we are talking about socio - political "connotations". Well, my understanding is that for any public health program including vaccine and vaccination - it has to convince the political and bureaucratic establishment, since they are the key decision body. This means - coming back to Dr. Sack's question - have we done better in this area of advocacy with those government, who need these vaccine. My opinion therefore is that we need to work hard to address the gaps in advocating OCV vaccine and its vaccination in a coordinated fashion, especially WHO, UNICEF, GAVI and other stakeholders like IVI, JHU - DOVE, We have to therefore act in unison rather than in a fragmented way. Here we can discuss more but i will halt here at this time.

However, we all also realize that Nepalese government has to remain vigilant and put its public health structure in order so we do not repeat the same situation that happened in Haiti some years ago. This is the key activity that should be put in place first, therefore disease surveillance utilizing the current system in place is the most important task. Should there arise the need for vaccination any threat of cholera, then we should think of vaccinating high risk population especially children. Importantly, we need to work with WHO to prepare for STOCKPILE mobilization from now on. For now, i would leave this post here. I think I would be in a better position to answer this question in next post based on "real field" experience like a somebody who has the same passion as Dr. Sack.

2nd May 2015 

Apr 23, 2015

Apr 18, 2015

My thoughts on business of cholera and impoverished community - Part 1 of 6 part series

I am writing this journal out of my own suffering at intellectual level. Now, I know - you definitely will ask me what kind of intellectual suffering? Well, this is a bit tricky - if I have to ventilate this out then I may sound caustic but on sober tone (please excuse me from being too radical!!) - I am in dilemma in all these business of cholera and other diseases inflicting impoverished community. After all, I hail from low income country and have closely observed the pain of suffering some of these easily preventable illnesses. Anyway, to bring context to what I am going to write and share with you all in this part 1 of the series on cholera, it is still my duty to explain some key technical words that I will be using more often in this write up for lay readers who are not used to these terms. I know some of us hate definition like Benjamin Disraeli (1804 - 1881) who says " I hate definitions". Well for us, it helps us provide better and clear understanding of the subject matter at basic level. Here I remember that one of our professor Ananthanarayan of Biochemistry used to say, "When your basic understanding of the subject is shaky - who will help you that I do not know !!" Now, we realize the truth of that remark almost 2 decades back. For my part, I still do not understand why Benjamin Disraeli had to hate definition? I take it may be he said so in literally meaning since he used be a free thinking writer and seasoned politician. I will refer to Leon Gordis' Epidemiology (4th Edition), and Vaccine (6th Edition) which I believe are equivalent to religious texts for those into vaccinology and epidemiology, along with other freely available online resources.
  • Epidemiology: The study of the distribution and determinants of health related states or events in specified populations and the application of this study to control health problems. Ref: Leon Gordis' Epidemiology (4th Edition)
  • Surveillance: Ongoing systematic collection, analysis, and interpretation of health data essential to the planning, implementation, and evaluation of public health practices closely integrated with the timely dissemination of these data to those who need to know. Ref: CDC definition
  • Vaccine: a preparation of killed microorganisms, living attenuated organisms or living freely virulent organisms that is administered to produce or artificially increase immunity to a particular disease Ref: online Marriam - Webster dictionary
So let us all go into basics before we talk more on cholera. This disease is caused by microscopic organism invisible to our eyes. You can say that this organism can be found in water that is contaminated by human fecal matter. So you can straight imagine those places where water and sanitation is in compromised state. For example we can take Kathmandu valley as an example where anytime in the future cholera outbreaks can occurs. However, there is also good signals to improve water and sanitation out of citizens active volunteerism to clean up Bagmati. Let us hope that this kind of cleaning river is not a political stunt for populism, it will be sustained and routine duty of people and government. Again back to micro - organism - this cholera causing organism is said to be of curved or comma shaped with a single flagellum at one pole. This disease is characterized by acute watery diarrhea and can lead to severe dehydration due to loss of water and electrolyte from our body. If s/he can not proper treatment with fluid replacement then s/he may also lose his or her life. This is still the case in low income countries with recent examples of Haiti (2009) and even in Jajarkot of Nepal. Also, remember this disease has potential for huge outbreaks that spread across geography facilitated by quick transportation across countries and even continent. So bottom line is that cholera is still a serious public health problem that can disrupt the socioeconomic activities and can lead to political backlashes to the government or other stakeholders. 

Since this blog focus on infectious diseases rampant in Nepal, I will focus rest of 5 posts on Nepal in relation to our understanding of this diseases connecting to broad public health perspective. In addition, I will also highlight my dilemma, where i think it deserves to be vocal. First thing first, let me try to dissect to key words in particular: business and impoverishment

Business normal sense is give and take activity in which there is an expectation of return once we invest certain figure of capital. So we think business in relation to money or capital return. However, I am using the word business in the sense of understanding what, how, when, where, why and who in the field of cholera academia. And, since cholera is related to poverty, which in turn impoverish in every aspect of community dynamics in terms of health, economy and social well being. In next post, I will touch upon the history of cholera and our understanding in Nepal.

To be continued......................

Apr 16, 2015

Summary of HEV and Nepal series

This disease may be new to you and may be you may just brush aside saying, "Well, this is none of my business!!" If you are thinking in that line, wait a minute!! Let me share you common suffering from this disease, which is rampant in low income settings. You may be avid hiker or trekker or you may also have a plan to travel to countries like Nepal, India, and Pakistan. When you get infected, whatever a person of strength and stamina, you will be bed ridden so quick that you have to get hospitalized for weeks. During this illness, you feel so miserable that you completely lose your appetite, lethargic, aversion to anything food or even its smell, and you turn yellow including your white of your eye bulb. Oh yes again, this disease is miserable, and it is said, this disease takes hold in your body after you ingest food or drinks that are contaminated with human soils. This happens in places, where when there is poor water supply, sanitation and hygiene practices. Remember, this may take the form of outbreaks affecting hundreds and thousands of people. The worst part is if this disease affects pregnant women. There is high chance of losing your pregnancy and even death of mothers due to liver complications that lead to fulminant hepatic failure and painful death. We know, this disease has not caught much of global attention like recent Ebola Virus Diseases, but remember, this disease is like a silent death that spread invisibly like bush fire with huge toll of illnesses and deaths in developing countries among impoverished population.

Where are we in its understanding?

HEV is a public health problem in low income settings causing havoc in many parts of the country. For example, let me share with you two outbreaks that provide clear perspective into the gravity of HEV problem in our country. One was the confirmed HEV outbreak in the premises of prime ministerial official residence in the year 2007, where then prime minister himself, cabinet ministers and other staffs caught this viral illness and bedridden for weeks. The second HEV outbreak is very recent in the month of May and April, 2014, which occurred in the heart of Biratnagar municipality in eastern part of the country. This outbreak was national headline, where thousands of municipality residence was taken ill and some of them died. In both outbreaks, the root cause for the disease outbreak was found to be the fecal contamination of drinking water. These two recent examples could provide us with a sense of urgency as to the extent of public health problem in Nepal that need to be addressed with available preventive tools. 

There are few facts I need to write for our memory and keeping facts straight before i conclude this series for next one. Here follows some facts on HEV:
  • Incubation period (IP) is approximately 40 days
  •  most important acute viral hepatitis among adults in much of central and southeastern  Asia and the Indian Subcontinent and the second most important hepatitis in the Middle east and North Africa
  • Up to 20 % clinical attack rate and an associated high incidence of fetal wastage
  • In endemic countries, genotypes 1 and 2 predominate and contaminated water is the major source of infection.
  •  Seronegative children and adults are at general risk of disease and pregnant women are at special risk for severe or fulminant hepatitis in endemic regions
  • With regards to vaccination - HEV vaccination is best suited to be included in EPI schedule rather than providing this vaccine in campaign mode. 

Before going into preventive measures available for this illness, let us try to delve into following discussion. To be more objective, I did a quick review of paper in PubMed and was fortunate to find series studies re: to HEV in Nepal since early 1980s. For our convenience, let us try to dissect these studies as below:

     Literature pre - 2000: Almost all studies were conducted and reported from Kathmandu valley from early as 1980s. Majority of the studies are hospital based done among admitted inpatients supplemented with serological test for its diagnosis. Few studies are also conducted among travelers or expatriate in the valley, Nepalese army in UN mission - Haiti and notably among pregnant women. One study was not human but done among local swine in the Kathmandu valley. The findings from these studies suggested that HEV is endemic in Kathmandu valley of significant public health importance and directly relates to poor water, sanitation and hygiene practices. Also, one study reports that local swine population is the host for this disease and suggests HEV as zoonotic illness. Another implication that these studies brings to our notice are that travelers / expatriates visiting Nepal are at risk; thereby this could affect tourism business. Also, there is every likely that the disease could spread to other geographical locations.

2   Literature post - 2000: All studies post-2000 add to HEV knowledge that have been gathered from studies in Kathmandu valley. What stands out in these studies is most of them are molecular in nature. These studies have clearly outlined the genotypic profile of HEV circulating in Kathmandu valley. Also, other studies done among pregnant women diagnosed with HEV infection adds to our knowledge that HEV remains serious threat to the health of mother and unborn child. Additionally, one study add that HEV has been detected to rodents in Kathmandu so adding to knowledge that some of the genotypes are zoonotic in origin, which later has implication in designing measures to control and prevention of this illness. Most important is that there was a conduct of HEV vaccine trial among Nepalese army. The vaccine tested in this controlled trial was “Hecolin” - which is licensed for use in China. 

With this background, I think, you can get a visual picture how common Nepali people must be living their life in rural impoverished community. Well, some month ago, when I wrote a brief note on cholera outbreak in some remote part of Terai, I got a public comment that it is not what I depicted in my writing. But we can hide the fact that there was an outbreak of significant impact in the communities. This we cannot deny and I hope one of my friends could be in a position to acknowledge that there exist challenges in clean water and sanitation delivery to the much needed people. However, we can debate on this public health issue. It can be controversial for those leaving in affluence. One contention I would like to bring out and be vocal outright with this background of long history of HEV studies with yearly outbreaks in Nepal, how long do we have to wait for this HEV vaccine?

Vaccine in Demand

The fruits of science have to be available for the community if the vaccine against HEV is tested in the same population during its clinical development. Before we go into technical jargon or say business case that is required for HEV vaccine to secure its place in WHO prequalified list so we can use this vaccine in public through UN agencies - let me walk you through some of the noise heard for this vaccine in Nepal. Of other countries, I cannot objectively tell or write now. But I can guess, same must be the case and scenario on other South Asian countries, where HEV outbreaks occurs yearly in impoverished population.

I Google - ed "HEV in News in Nepal" - I came across pretty long list of online news or even oped pieces. One stand out among those read and is written by Dr. Buddha Basnyat in Nepali Times. This opinion piece (#Issue 591 - Feb 2012) strongly states on possible public health use of HEV vaccine (in Nepal) comparing with SA 14 - 14 - 2, live attenuated vaccine against Japanese encephalitis (JE) also produced and licensed in China. This vaccine was also not WHO pq ed at the time when Nepalese health authority decided to use it country wide in endemic districts. This JE vaccination started in campaign mode and later introduced into routine immunization. This way, JE vaccination has been a successful program in controlling and preventing debilitating serious brain viral infection. Now, we see such a visible public health impact that anybody when travels to Terai districts can hear such stories of success. The strength that lies hidden in this endeavor is the background surveillance of Acute Encephalitis Syndrome (AES), which provided clear picture as to the epidemiology of this disease, so policy makers were able to provide direction for the country. If so is the case for HEV vaccination in Nepal, my only question is “Do we have such robust background surveillance data to guide our policy makers so they can take policy decision?" Otherwise, i can agree to what Mr. Basnyat point of view, when another HEV vaccine which was tested in Nepalese population - why not make Hecolin (Chinese vaccine) available for public health use here in Nepal? 

One key constraint is lack of comprehensive surveillance data to back up our argument for introducing HEV vaccine in the community especially vulnerable population. So, for me, I would love to see comprehensive epidemiological picture of HEV across the country. Therefore, one way would be to review all the literature so far published and use modeling tools, or conduct surveillance (active vs. passive) based on availability of budget aligning with interested parties to gauze and weigh the gravity of HEV problem in Nepal. Let us see how far this will go or else may be, there must be a way to extrapolate the findings of other country experience and create public demand for this vaccine. In that case, the recent outbreak of HEV in Biratnagar could be one scenario; we can build one for effective advocacy.

Where are we in its vaccine development?

When we remember those days of extreme weakness with bouts of vomiting with incessant nausea that gripped your guts, we can now feel the suffering. However, it is comforting to know so much have been studied on HEV and we do know the basic epidemiology including the genotypic mapping of HEV circulating in Nepal. Notably, some of the human phases of clinical trials were also conducted in Kathmandu among Nepalese population. 
However, there is only one voice that we have heard and now I have started to understand why the candidate vaccine meant for HEV is still not there in public health or even in private market arena? In this aspect, I read a short letter in response to a paper published in a leading science journal. Dr. Buddha Basnyat (a senior scientist seriously studying infectious diseases in Nepal) has raised a serious ethical question as to why vaccine industry or research organizations who have invested so much of their time and money to develop HEV vaccine and now, there is no vaccine when there is high demand in the community. In the letter titled Neglected HEV and Typhoid Vaccine, he raises a serious question, “These vaccines against hepatitis E.......are not available, despite their proven efficacy and safety. If GSK, Walter....were not going to develop these vaccines or make them available after their successful testing in Nepal and Vietnam, why were they tested? And if these organizations will not develop them further, is there a responsibility to make them available to others who might?"

Nitty Gritty of HEV

HEV is an area that needs much advocacy from the community and national level like Nepal / India / Ethiopia, where HEV is still serious public health issue. We should not wait for it instead we need to advocate to the global health community. This is what i have been saying we should work simultaneously from both end - at international fora as well build base at the community level and have find a meeting point where international authorities and community health leaders can sit together and have a meaningful but fruitful outcome from all the penny invested in such study re: HEV or any other vaccines.

I think, I have shared enough about HEV outbreaks in Nepal. Now, at my personal level, a concrete research concept is what the need of the hour along with active collaboration with academician and public health professionals in Nepal. For this, we need to review papers so far published re: HEV in Nepal and find out knowledge gaps where we need to address. Also, the key to what we plan can only be successful if we partner with international organizations, who can advocate on this problem at an international forum. 

Therefore, this planned review (that we need to write) has to bring out the comprehensive HEV epidemiology in Nepal. It should also incorporate opinion from all stakeholders, who has a role to play in bringing this much needed vaccine to the community. Finally, we need to acknowledge that there is a huge demand for HEV vaccine in countries like Nepal, Ethiopia, India, Myanmar. This has been spelled out by leading physicians and researchers in Nepal as well. The only remaining challenge is whether the voice of demand for HEV vaccine has reached those who invest or has resources to focus available fund in this area or not? I think, it has reached and it all lie within us how efficiently advocate on this HEV issue at national or international level. Importantly, I believe we have to raise awareness in the national as well as community level.

Anuj in Himalayas

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