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  • Ronan Kelly
    replied
    Thanks JJackson - your thoughts are very much appreciated. For a while there, India was blanketing all contacts of H1N1 cases with Tamiflu. In 2015, at least 68,500 patients were prescribed Tamiflu in Maharashtra alone. I wonder how many of those courses of treatment were not completed or shared. I'd be curious to see to what extent Oseltamivir resistance has changed over time. From the paper at the top of this page 2 of 12 fatal cases showed resistance. I agree that the effect of many mutations to the influenza genome are insignificant. I'd also welcome expansion of India's surveillance system to include public reporting of other influenza strains so that we could compare the effect of an H1N1 dominant season to an H3N2 dominant season for example. If wishes were fishes...

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  • JJackson
    replied
    Ronan I have no relevant formal training in virology or sequence analysis, but for what it's worth, I think the C1, C2 part of the reply relates to the passages and passage medium and I have pasted below part of a reply I made to a question of Mixin's in this thread on vaccines in my work shop.
    The collected flu sample is grown in the lab in chicken egg cells (C) or some other cell line like the mammalian line (MDCK) where C1 would be the first passage in an egg medium and its product would be the input for C2 etc.
    It is important in understanding the trends in the sequences while they may drift during passage there will be limits to how far.


    Flu is famous for its ability to mutate so if you have a swab and grow it in X – where X is one of MDCK, SIAT, egg or some other cell line – you are going to get a whole range of variations around whatever was in the swab. All of the virions produced will then have to find a new cell to infect in the growth medium but which of this generation succeed will depend, at least in part, on how well adapted the RBS of their HA is to whatever X we happened to choose. The reason we have to passage the virus at all is the swab sample size is too small. Each generation is termed a passage and each passage produces more virus but it also increases the chance that the virus will drift away from the sequence we would have got if we had been able to exactly clone the original sample (I am ignoring the whole quasi species aspect of flu to keep it simple – think of it as adding an extra passage).

    From the above we can see that what comes out is not necessarily identical to what went in. The question is how different is it? That depends on two main variables how many passages were performed and how strong the selection pressure was. To minimise the drift we can reduce the number of passages – for which we either need a bigger initial sample or we can increase the diagnostic sensitivity (needs less product) – and/or we can reduce the selection pressure by making sure we match, as accurately as possible, our passage cell line to the samples host species. There is no perfect match for a human flu virus sample; egg would be worse than MDCK which would not be as good as SIAT. There is a limit to the amount of drift you are likely to get so you will end up near the ideal but not exactly on target.
    Now if you use your product in an HI test then original samples which were already further away from the test antisera are more likely to have drifted over the border into 'low reactor' territory. Conversely on remote branches of the phylogenic tree could – which would have been low reactor – samples may passage back into the more central zone.
    The extract is from post #7 and there is more relevant information in the thread but some of it is more technical and relating to Mixin's specific question.

    On the more general aspect of 'mutations' or 'no mutation' on the HA.
    There are always mutations in the sequence data the question is are they significant? Some areas on some of the RNA strands are known to correlate effects on biological function however, sadly, these are only guides and do not always have the same degree of influence on all genetic backgrounds. H1N1(2009), for example, has a very well know avian sequence on its PB2 strand which should make it reproduce poorly in mammals and I expected it to mutate rapidly to the mammalian form but it has remained stable proving that on this strain the change is not critical.
    Over the last decade I, and many others, have written extensively here on many aspects of problems relating to the sequence databases and the interpretation of sequence data. If you, or anyone else, have questions relating to this area please ask them below and I will try and write something or find a link to a remembered post covering that aspect.
    As always, in awe of your work on collating data on India's disease burden. JJackson.
    If it would be helpful to your work I would be willing to attempt an analysis of any Indian H1N1 data at GISAID & Genebank but I am a little doubtful there will be firm conclusions - I suspect the CDC analysis is correct there were mutations but none of known significance. Markers for Oseltamivir resistance are well known, easy to spot and would have been reported. PM me if you think I could help along with any time periods and specific areas of the genome. Even if anything genetic had occurred it would seem to have been out performed by another wild-type and removed from the gene pool as the spike has not persisted or spread geographically.
    Last edited by JJackson; March 7, 2016, 11:23 AM.

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  • Ronan Kelly
    replied
    EMERGENCE OF INFLUENZA A(H1N1)PDM09 GENOGROUP 6B AND DRUG RESISTANT VIRUS, INDIA, JANUARY TO MAY 2015

    ...
    Discussion

    Influenza A viruses have been responsible for four influenza pandemics in last century viz., Spanish influenza (H1N1) in 1918, Asian influenza (H2N2) in 1957, Hong Kong influenza (H3N2) in 1968 and pandemic influenza (H1N1) in 2009, which was caused by influenza A(H1N1)pdm09. During the 2009 pandemic period (2009?2010), India was affected with around 50,000 cases and a case fatality of 6% [12]. After the end of the 2009 pandemic, the virus continued to circulate at low level in the population, and during the period from 2011 to 2014 the circulation of the virus declined [13]. From January to May 2015 however, over 39,000 persons in India were affected by a new epidemic of influenza A(H1N1)pdm09, with more than 2,500 deaths [1]. The outbreak spread across 22 of the 29 states in the country, making it the largest since 2009. This sudden re-emergence and wide spread simultaneous reporting of influenza A(H1N1)pdm09 along with higher number of hospitalisations and deaths was a major public health concern.
    By further characterising the strains infecting patients positive for influenza A(H1N1)pdm09 through HA phylogeny, this study finds that sequences of genogroup 6B were circulating during the 2015 epidemic. The genogroup 6B was found to evolve from a Russian isolate (A/Moscow-Oblast/CRIE-08/2013) and is since then circulating in many parts of the world. However, this is the first report from India regarding circulation of genogroup 6B, coinciding with a large scale outbreak [1].
    Researchers from Massachusetts Institute of Technology (MIT) have recently reported mutations D225N, and T200A in a 2014 Indian strain (A/India/6427/2014, which also clusters with genogroup 6B sequences in the phylogenetic treeFigure 1) making the virus more infectious [14]. Although we did not find these two mutations in our study, all the sequences that we characterised harboured five mutations (P83S, I321V in HA1, as well as E47K, S124N, and E172K in HA2), which although previously described, have not been reported in combination. Moreover, two isolates from patients with severe disease harboured a N129D mutation in HA1 and two isolates had a mutation in HA2, E164G, that has not been observed to date. These unique features of the viruses found here may have played a role in shaping the large scale epidemic with cases of severe disease. On the other hand, the 2015 epidemic in India may be attributed to lack of immunity among an immune-na?ve population. It is also noteworthy that seasonal influenza vaccination is not very common in India.
    Some limitations of the study include that the samples were only tested for influenza A(H1N1)pdm09 virus, whereby only 38% of samples tested were positive. Therefore, co-circulation of other influenza subtypes or types could not be ruled out. Moreover the sequence analysis was conducted with only few positive samples that did not cover other gene segments than the HA and NA genes.
    The influenza A(H1N1)pdm09 virus represents a quadruple reassortment of two swine, one human, and one avian strain of influenza virus [15]. The largest proportion of genes comes from swine influenza viruses (30.6% from North American swine strains, 17.5% from Eurasian swine strains), followed by North American avian strains (34.4%) and human influenza strains (17.5%). It will be interesting to investigate the involvement of any gene reassortment in the 2015 outbreak in India through complete genome sequencing.
    Two of 12 strains from fatal cases were found to harbour a mutation conferring resistance to oseltamivir. Learning more about the 2015 strains circulating in India could help public health officials determine treatment options and inform on vaccines for the next influenza season, which is likely to include currently circulating strains [16].
    Our findings show the importance of systematic molecular surveillance to provide insight into strains circulating during influenza epidemics.

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  • Ronan Kelly
    replied
    Last Modified: Fri, Mar 20 2015. 11 51 AM IST
    The curious case of the H1N1 mutation
    India?s rejection of an MIT study on swine flu reveals a transcontinental trail of unanswered questions about the genetic data involved
    ...
    I reached out to Ram Sasisekharan, a professor of biological engineering at the Massachusetts Institute of Technology (MIT) in Boston, to talk about the growing dread in India about H1N1, popularly called swine flu.
    ...
    Had a mutation occurred in India to explains H1N1?s greater virulence? When I spoke with him last month [Feb 2015 - Ro], Sasisekharan said it was hard to tell because there was little or no ?sequence information? on the Indian H1N1 strain circulating in global, genetic databases. This was frustrating, he said, because such information-sharing allowed collaborative efforts, which were key to surveillance, management and predicting the spread of the virus. Back in India, the only information made available by unnamed scientific sources in a couple of newspapers was that H1N1 genetic sequences with the National Institute of Virology (NIV) in Pune showed no mutations.
    ...
    On 6 March, MIT public relations alerted me?one of many heads-up that I get from scientific institutions around the world; in India, I get none?to a forthcoming paper from Sasisekharan.
    ...
    His paper?published in Cell Host and Microbe, a global scientific journal?essentially said that the Indian H1N1 virus, a genetic sample of which he had obtained from a global database, showed changes in a gene called heammaglutinin, known to mark virulence. In other words, the Indian virus may have mutated, which might explain the unexplained virulence and unprecedented death toll (although the infection rate, compared to 2010, is not particularly worrying for a flu outbreak). The paper also noted that India ranked a low 14th in a global list of contributors of complete H1N1 genetic sequences.
    ...
    the government?within 24 hours?put out a press release. It denied there were any mutations.
    ...
    Neither did an analysis of the virus by the US Centers for Disease Control and the World Health Organization report genetic changes or resistance to oseltamivir, the main anti-H1N1 drug, the release said.
    ...
    ?I think you can have a look on passage level C1 & C2 also.? The GISAID database did have that entry. I asked him what he meant. He never replied, but his implication was that the genetic sequence that the MIT scientists used was not original and hence unreliable.

    This kind of a defence--if you can call it that--only raises more questions:

    Since NIV has samples of the H1N1 virus panicking India, why does it not release the genetic sequences? The H1N1 virus? proclivity to mutate is now common scientific knowledge, so--instead of running down warnings--does it not make sense to share its current and evolving genetic profile? Given the dangerous global history of influenza, should not worldwide collaboration be a preferred option to bland, unconvincing denial?

    The quicker NIV and India?s government start answering these questions, the better.

    Samar Halarnkar is editor of IndiaSpend.org, a data-driven, public-interest journalism non-profit. He also writes the column Our Daily Bread in Mint Lounge.
    http://www.livemint.com/Opinion/PyAP...-mutation.html

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  • Ronan Kelly
    replied
    Agreed, no consensus and I haven't seen any more recent papers than June 2015. Doesn't mean they aren't out there. There are 681 hits for "India H1N1 2015" at GenBank, but I'm afraid I cannot interpret the results. Most seem to be partials. I presume there are others at GISAID. I'm really not sure how comprehensive the surveillance network is. There is nothing like a national "FluView". Some states publish numbers, some don't. I'm not sure how well funded it is or whether it exists in name only. Information on flu types other than H1N1 is hard to come by.

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  • JJackson
    replied
    Ronan they do not seem to reach a consensus as to the cause of the spike. On a more reassuring note none of them single out antigenic drift as a significant problem.
    Do you know what the sequencing regime is like? I recall you did not have a high opinion of it before but one of these papers seemed to think it was working.
    ... along with the molecular surveillance of the influenza virus circulating strains which is already ongoing in India through an established influenza surveillance network.
    also do you know where they are submitted GISAID, Genebank or internally.

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  • Ronan Kelly
    replied
    Influenza Surveillance: 2014–2015 H1N1 “Swine”-Derived Influenza Viruses from India
    Kannan Tharakaraman, Ram Sasisekharancorrespondenceemail
    DOI: http://dx.doi.org/10.1016/j.chom.2015.02.019 |
    Article has an altmetric score of 271 4
    Summary
    Full Text
    Images
    References
    Summary
    The 2014-2015 H1N1 outbreak in India has reportedly led to 800 fatalities. The reported influenza hemagglutinin sequences from India indicate that these viruses contain amino acid changes linked to enhanced virulence and are potentially antigenically distinct from the current vaccine containing 2009 (Cal0709) H1N1 viral hemagglutinin.
    http://www.cell.com/cell-host-microb...128(15)00076-1

    J Glob Infect Dis. 2015 Apr-Jun; 7(2): 56–59.
    doi: 10.4103/0974-777X.157236
    PMCID: PMC4448325
    2015 Resurgence of Influenza A (H1N1) 09: Smoldering Pandemic in India?
    Baijayantimala Mishra
    ...
    CONCLUSION
    The present resurgence of pandemic virus cannot be attributed to any single factor at this stage. The prolong cold and dry weather, possibility of drift virus, absence of annual flu vaccination could have played an integrated role in resurfacing of pandemic virus. The role of sero-epidemiology should be given its due importance for vaccination policy along with the molecular surveillance of the influenza virus circulating strains which is already ongoing in India through an established influenza surveillance network. Vaccination campaign, public awareness and education measures should continue in an optimum mode, even during the inter resurgence interval period, balancing the necessity vis-a-vis public panic. Lastly, considering the ecology, epidemiology, molecular biology of the pandemic virus, a modeling system should be developed to predict such resurgence in future and building up of herd immunity against all the circulating influenza viruses along with pdm H1N1 is essential to fight the battle with the virus.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448325/

    Dynamics of Influenza Seasonality at Sub-Regional Levels in India and Implications for Vaccination Timing
    Mandeep S. Chadha , Varsha A. Potdar, Siddhartha Saha, Parvaiz A. Koul, Shobha Broor, Lalit Dar, Mamta Chawla-Sarkar, Dipankar Biswas, Palani Gunasekaran, Asha Mary Abraham, Sunanda Shrikhande, Amita Jain, Balakrishnan Anukumar, Renu B. Lal, Akhilesh C. Mishra

    Published: May 4, 2015DOI: 10.1371/journal.pone.0124122
    ...
    Conclusions

    Our data shows that India, though physically located in northern hemisphere, has distinct seasonality that might be related to latitude and environmental factors. While cities with temperate seasonality will benefit from vaccination in September-October, cities with peaks in the monsoon season in July-September will benefit from vaccination in April-May. Continued surveillance is critical to understand regional differences in influenza seasonality at regional and sub-regional level, especially in countries with large latitude span.
    http://journals.plos.org/plosone/art...l.pone.0124122

    Reemergence of Swine Flu H1N1 in India: First Outbreak
    of 2015

    Sharma RB and Husain M*
    Department of Biotechnology, Jamia Millia Islamia
    Central University, India
    *Corresponding author: Husain M, Department of
    Biotechnology, Jamia Millia Islamia Central University,
    India
    Received: June 25, 2015; Accepted: September 24,
    2015; Published: October 03, 2015
    ...
    Conclusion
    The current review focuses on the re-emergence of H1N1 virus
    that has caused morbidity, mortality and socio-economic loss to the
    world during its pandemic phases. Again the same virus has alarmed
    in India from January 2015 by infecting thousands of people with
    severe mortality. Though the country prepared in terms of diagnostic
    and preventive measures but there is no such data available which can
    narrate the current scenario of influenza immunization in the high
    risk group or in general population. Although the control measures
    for flu seems to be very unyielding as it is airborne and able to
    transmit easily and rapidly in Indian scenario. As the influenza virus
    is very prone to genetic shift and drift, its mutation, transmission and
    spread is impossible to control but taking proper preventive measure
    can reduce the disease severity and economic burden. Annual
    influenza vaccination to all would be a good preventive measure but
    if not possible at least high risk group (children, health care workers,
    elders, immune-compromised etc.) should receive it. Designing viral
    conserved region based vaccines would be more helpful to protect
    against all influenza strains as well as against novel pandemic strains.
    https://www.google.com/url?sa=t&rct=...16274245,d.cWw

    H1N1 Revisited After Six Years : Then and Now
    Shobha Itolikar1, Milind Y Nadkar2
    1Asst. Prof., 2Professor, Dept. of Medicine, Seth GS Medical College & KEM Hospital, Mumbai, Maharashtra
    Received: 12.03.2015; Accepted: 13.03.2015
    ...
    Are we Seeing Tip of the Iceberg?: There are several factors that make it difficult to determine accurately the numbers of deaths caused by flu regardless of reporting. Some of the challenges in counting influenza-associated deaths include the following: the sheer volume of deaths to be counted; not everyone that dies with an influenza-like illness is tested for influenza; and influenza-associated deaths are often a result of complications secondary to underlying medical problems, and this may be difficult to sort out.5
    ...
    http://www.japi.org/april_2015/08_ua...after_six.html

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  • Ronan Kelly
    replied
    So one year later looking at figures for 2016 we do not see such huge numbers being reported. This strongly suggests that 2015 was indeed an epic year for H1N1 in India and not just a result of improved surveillance. Would be interested to see if any studies follow this up.

    IndiaGISRS.png
    http://gamapserver.who.int/gareports...spx?ReportNo=7

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  • Emily
    replied
    I agree it would be nice to have some context to those numbers. There does seem to be an increase in testing for 'swine flu' this year.

    "These laboratories and hospitals are taking undue advantage of the situation. Last year, the trend was totally opposite as just one case of the influenza was reported from the city. But this year, more and more people are getting themselves tested for swine flu, even as a precautionary measure. With the scare looming, these private labs and the hospitals are making money," a health department official told MAIL TODAY.

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  • Ronan Kelly
    replied
    Thanks for linking that story Emily. It's a very nicely written article. What I get from it is that the MIT group has made their findings public in a peer reviewed paper and released their sequences to GISAID. The NIV has denied that the mutations are in the original sequences, but has not released those sequences.
    Update: The CDC has now also agreed that the mutations are present, but do not automatically imply more severe disease. https://flutrackers.com/forum/forum/...514#post728514

    The whole idea of improved surveillance in India is moot without some sort of guidance from The Indian CDC or MOHFW. We simply don't know. What is needed is an analysis of the raw figures. But that would involve a paradigm shift for Indian healthcare & politics. Because they rely on those absolute figures. India compares absolute numbers year to year regardless of the testing regime, regardless of reality some might say. Some states deliberately discourage testing to make their reportable disease numbers better. What we do know is that testing for strains of Influenza other than H1N1 rarely happens. This glaring absence argues against an improved surveillance and testing regime. And that 37.5% positive test number from Karnataka suggests a pretty significant flu season.

    Then there's the WHO who publish the chart below each week. Surely this glaringly large influenza season needs to be investigated more thoroughly! You know that if the American CDC produced a chart like this without explanation, there would be a widespread cry of Why? What's going on? But with India, it's always just - Meh, probably nothing. Sure doesn't look like nothing. GISRS 2.png



    http://gamapserver.who.int/gareports...spx?ReportNo=7
    Last edited by Ronan Kelly; April 3, 2015, 04:12 AM. Reason: See Update

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  • Emily
    replied
    I would guess that some of the reported H1N1 flu mortality in India could be due to better testing, but don't doubt that there could also be an unusual age group effect. We had that in 2013-2014 and the best theory I read on that was the 'original antigenic sin' theory. (Based on early exposure to that 1977 lab escape H1N1.):

    http://www.pnas.org/content/111/44/15798.full

    So perhaps India is experiencing this phenomenon this season. So far I haven't seen anyone independent of potential financial conflicts of interest promoting fear of anything more than this.

    https://in.news.yahoo.com/hello--any...104901301.html
    What about panic stations?
    Meanwhile, is it a good idea to get vaccinated? The MIT paper is an opinion piece that calls for greater surveillance, but also speaks of "widespread vaccine campaigns" as a strategy to tackle influenza.
    Sasisekharan, the corresponding author for the MIT paper, is a well-known scientist and professor of biological engineering at MIT. He’s also a biotech entrepreneur who founded the company Visterra, which is working on an influenza A vaccine (H1N1 is a subtype of influenza A) and, according to the MIT News Office, possibly laying the ground for a universal influenza vaccine. The MIT paper ends with a small acknowledgement that Sasisekharan is on Visterra's board. When an Indian newspaper asked him about the Indian government's hints that he had an agenda to push by suggesting H1N1 had mutated for the worse, he wrote, “It has no relevance to this study.” Sasisekharan did not respond to emails from this reporter seeking his comments on the subject.

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  • Shannon Bennett
    replied
    I just read the full text of a Tetano import re. the stats for age and gender study of severe flu cases in China between H1N1 and H7N9. http://journals.plos.org/plosone/art...l.pone.0120999

    The H1N1 stats were both surprising and unsettling. They were younger and had fewer prior complications of ill health. That included such conditions as asthma, diabetes, ... Why is H1N1 hitting us so hard?

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  • Shannon Bennett
    replied
    I think we are going to find that this was a bad year in most countries with the number of flu deaths. The number of deaths in otherwise healthy people in their prime is very disturbing.

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  • Ronan Kelly
    replied
    New data from Maharashtra released yesterday on fatality demographics. A significant number of deaths in women aged 20-40. 85% of all deaths were aged under 60 years old.
    https://flutrackers.com/forum/forum/...294#post728294

    And from Karnataka showing that the % positives this year is far higher at 37.5% than any other year including the pandemic. Also, Bangalore accounts for 38 of the 85 deaths (44.7%), but 71.9 % of the positive tests. This suggests to me that testing outside of the major urban areas may still be lacking.
    https://flutrackers.com/forum/forum/...406#post728406

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  • Ronan Kelly
    replied
    I agree. We just don't have the data to say for certain, but....

    A report from Madhya Pradesh indicates that 43 % of fatal cases were aged 16-40 years old;

    Swine Flu: Death Review report was shocking, 43% of young victims
    Rohit SrivastavaMar 17, 2015, 01:56 AM IST

    Bhopal. However, the Government of the young swine flu infection is excluded from the list of high-risk patient, but the reality is the opposite. Swine flu deaths in the state, including the capital, 43 per cent are young. Their age is between 16 and 40 years. Analysis revealed that swine flu death reported to have occurred in the control room. Ripaert the youth because of swine flu infection disease at the beginning of the transition is to ignore him.

    Swine Flu: Death Review report was shocking, 43% of young victims
    ...
    https://flutrackers.com/forum/forum/...102#post727102
    Last edited by Ronan Kelly; April 3, 2015, 02:01 AM.

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