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May 8, 2015

Post Earthquake Preparedness against possible Infectious Diseases Outbreaks in Nepal

Now I am in Nepal. Today is my 4th day here in Kathmandu. Over these days, I visited key government offices and expressed to directors, "how we can be of assistance to Government of Nepal (GoN)? Also, we stated our competencise, which can be used in case disease outbreaks should occur in Earhquake hit areas. After thorough discussion, my impression (as of now) is that GoN is working hard to address this emergency situation judiciously. The key aspect we need to understand is that the overall coordination of the relief work is being conducted through National Emergency Operation Centre (NEOC), while the health related activities are being coordinated through Health Emergency Operation Centre (HEOC), which are supported by all key international multilateral organizations like WHO, IVI, UNICEF and other UN organization, bilateral organization  and local NGOs and volunteer from many countries. HEOC is spearheaded by Ministry of Health along with other key departments and divisions. Special mention should be Epidemiology and Disease Control Division (EDCD), this division is working hard to control possible infectious diseases outbreaks like cholera, dengue, leptospirosis. To assist GoN, IVI along with WHO, UNICEF, CDC, JHU and GTA (group for technical assistance) is coordinating closely to tackle possible cholera outbreaks in affected districts in Nepal. Key activities that need to be done at the moment are assessment of cholera risk and then present the findings in Enteric Diseases Steering Committee under the leadership of Director General (DG), Department of Health Services. Surveillance is being strengthened and EDCD and WHO are working closely to pick possible outbreaks at the earliest. There is clear directive from the ministry of health to report all reportable infectious diseases SOS without hesitation. GON (at EDCD) along WHO / IVI / UNICEF / JHU / GTA will work hand in hand to mobilise WHO stockpile of cholera vaccine available. 

Key activities that I have been involved as of now:

Relief Camp in Bhaktapur (Photo courtesy Anuj Bhattachan)

5th May 2015: On this day, we had a meeting at EDCD (along with IVI / WHO /GTA). Also, visited WHO Program for Immunization Preventable Diseases (IPD) and Sukra Raj Tropical Hospital, Teku. I met Dr. Sher Bahadur Pun, Infectious Diseases Specialist, who shared his experiences and expressed opinion re: landscape of infectious diseases that report in the hospital. He says that yearly sporadic cases of cholera have been reported in KTM valley.

6th May, 2015: On this day, we had a meeting at Child Health Division (CHD) along with representatives from UNICEF, WHO. In the afternoon, I visited GTA office to prepare concept for tackling infectious diseases outbreaks which is highly possible aftermath of Earthquake in Nepal.

7th May 2015: I had meeting with Rotary Nepal to discuss on IVI Rotary Project that we have planned for Nepal. I also understand, we need to work hard to convince people from different background so we can immunize people from cholera or other vaccine preventable diseases (VPDs) in impoverished community. In the afternoon, we again had follow up meeting at GTA for the finalization of the concept note.

9th May, 2015: I visited Kamal Binayak Camp in Bhaktapur in response to possible cholera outbreak. The key issue after a preliminary report shared by one of senior epidemiologist has created noise among public health professionals involved in surveillance of reportable infectious diseases. The main concern is laboratory investigation of stool samples collected from those camps in the vicinity of Bhaktapur. We hope that the results of the stool examination will be openly shared and acted upon it.

May 4, 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

May 3, 2015

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)

Anuj in Himalayas

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