Wednesday, October 24, 2012

OCV: Oral Cholera vaccine


    Recently the 2012 Nobel prize winners were announced to well deserving candidates. The recipients include  (Link)
  1. John B. Gurdon and Shinya Yamanaka for study on stem cells
  2. Robert J. Lefkowitz and Brian K. Kobilka for studies on G coupled Receptors
  3. Serge Haroche and David J. Wineland for experimental methods that enable measuring and manipulation of individual quantum systems
  4. Mo Yan in Literature
  5. Alvin E. Roth and Lloyd S. Shapley "for the theory of stable allocations and the practice of market design".

Photo 1: Hisashi Moriguchi (Source)
      Hisashi Moriguchi is all over the news and almost everyone has talked about it. His claims on stem cells research was suspicious enough to come under a check. His subsequent retraction of the claims further strengthened the "claims were fake"and invited himself to be fired off from the institute he was working. The material was also calculated to be plaggered and represents a scientists pressure to perform. More story here and here.
     I have a strong note to make that is my day to day experience many a number of times. I have seen people (especially students) wearing their laboratory coats outside the laboratory. You could see them roaming with such coats even in malls. They probably think it is a fashionable material. I often wonder at this. There has been multiple studies throughout the world showing such behavior is potentially hazardous. For example take this study published in JCDR recently. Am specifically making this note because, I cannot stand this behavior and i have strong feeling that such people should be scrutinized for pathogen dissemination and considered as intentional Bio-weapon act.

     A recently published article in mBio (ASM press), by Njoroge etal, shows something that i have never thought of. The study shows how a enterohemorrhagic E coli, EHEC uses a system for sensing sugar metabolites to turn the AE (attaching and effacing) lesions on enterocytes- making machinery on or off. All the articles in the Journal of mBIO is open access and hence i strongly recommend that you read it. The same journal also features a set of arguments (Special issue) on Influenza research (Links 1, 2, 3, 4, 5, 6) that provides perspectives from various angles of science.

Photo 2:  B subtilis (Source)
    Another segment of interest is vaccine deliver vehicle- "B subtilis". A team of scientists from Royal Holloway, University of London has come out with a novel idea of delivering antigens using a bacterial systems. And unlike the traditional needle delivery this maybe used as a nasal spray systems.  Professor Cutting commentsBacillus based vaccines offer distinct advantages as unlike other approaches, oral delivery can cause a more specific immune response in the gastrointestinal tract to fully eliminate C.difficile.”

     The next interesting article that i want to bring to your notice is from Lancet. HIV and tuberculosis goes hand in hand. A low cost, rapid and sensitive detection of TB would be an excellent option in HIV suffering patients. This study by Jonathan and team, has estimated the possibility of use of urinary sample to detect lipoarabinomannan antigens (TB-LAM). The study also comes with comments and authors response, here and here

Photo 3: TB-LAM test and reference scale card (Source)
     With that let me come into a study published again in Lancet on "Oral cholera vaccine" (Link). The article has brought in me a sufficient set of strong interest, because, cholera is a very devastating disease. Let me start with some background on V cholerae.

Cholera bacilli:

Fig 1: Mechanism of CT action (Source)
     V cholerae is a gram negative curved (Referred as comma shaped) bacilli, well known for its darting motility. An infection with this bacilli, leads to watery diarrhea, (Rice water stool appearance). The bacteria is a non invasive, self limiting gastro-intestinal pathogen. But the devastating effects are caused by a toxin- Cholera toxin (CT). Interesting enough, the bacteria thrives well in marine conditions. I always envision, the production of CT as a mechanism of making the gut marine like (By liberating ions and bringing a alkaline pH), so the bacteria enjoys the stay. Moreover, the CT coding gene is not a natural bacterial product, but a gene donated by virus. The virus is CTXφ (Reference).

    There are 2 biotypes of V cholerae O1 group- Classical and El Tor. The classic type was much milder in its properties, and El Tor is an improved version. 524 genes (13.5% of the genome) is differentially expressed in two biotypes. Most of them links to the biological activity. This probably accounts for the difference in pathogenic capacities of the two (Reference).

     This nasty bacteria (Cant find a better deserved word), has spun a total of 7 documented pandemics in last 200 years (Link). In 1992, A new strain of V cholerae serogroup O139 emerged and was referred to as Bengal strain.  The strain, originating in Madras in late 1992, O139 Bengal of V. cholerae has rapidly become epidemic throughout many areas of South Asia since 1993 and threatens to become the 8th pandemic. That means we are expecting an 8th pandemic.

Photo 4: Dukoral vaccine
      Vaccine is always an attractive candidate when feasible. Two vaccines exist that is approved for use in humans against cholera.  Dukoral is manufactured by Crucell company. First licensed in 1991 and available in more than 65 countries for use.  Dukoral consists of two components

1. Heat- and formalin-killed whole-cell V. cholerae O1 Classical and El Tor. The combination induces mucosal IgA antibacterial immunity, which interferes with colonization and adherence of cholera vibrios to the intestinal epithelium.
2. Recombinant non-toxic B subunit-binding portion of the cholera toxin (Cholera toxin B subunit), which is known to induce protective antitoxic IgA immunity.

Photo 5: Shanchol
    The second vaccine that has been approved by WHO is Shanchol, manufactured by Shantha Biotechnics. The product was licensed for use in 2009 and has been efficacious, costing US$1.85 a dose. The product had also won the BioSpectrum Asia Pacific Bioscience Industry Product of the Year Award for 2010. In comparison to Dukoral, this is a bivalent vaccine against 2 serogroups O1 and O139. The advantage over the former, is that it doesn't have to be ingested with a buffer.

      The expected advantage of Dukoral over Shanchol is a partial protection over ETEC, because of B subunit in the vaccine.  However, Shanchol produces a long lasting immunity, and doesn't require booster doses every 6 months. To read more about Cholera vaccines, go here

     The study under talk here was conducted in Zanzibar (Map shown to the right). A total of 48178 people (of 56620 registered candidates) were found to be eligible for study and a massive vaccination campaign was launched using Dukoral (rBS-WC) vaccine. The vaccine consisted of 1 mg of recombinant cholera toxin B subunit and roughly 10¹¹ inactivated whole cells of Vibrio cholerae O1 Inaba and Ogawa, classic and El Tor strains. Two rounds of vaccination was carried, such that people received 2 doses, with a minimum of 12 days between the 2 doses. Only 23921 people received both the dose.

      The study measured direct and indirect protection afforded by the vaccine. All the cases that seemed to be a diarrhea was carefully evaluated by standard laboratory procedures. Ultimately, the study found that the recipient of both dose had protection of  79%, and 46% in single dose recipients. But the following statement has bothered me.

"Surprisingly, we noted that not only did the vaccine not protect against non-cholera diarrhoea as expected, but also receipt of the vaccine was associated with a higher risk of non-cholera diarrhoea".

       Now this is something which is against the original claims of vaccine manufacturers. The authors propose that this could have been simply because the people selected was not random, and the people who were participating where originally willing to do so, because they had an increased risk. I thought that not having a Vibrio there might have given competitive edge to other bacteria that can then cause a diarrhea. Yes, it is arguable, but i cannot eliminate this possibility by looking at the provided results.

   But, what this article means to me is that Dukorol is efficacious to use, and with a better hygienic conditions also, the use may yield good results. But in context of India at least, i had still prefer, Shanchol. That is because Shanchol has O139 component, which is expected to be 8th pandemic.

ResearchBlogging.orgKhatib AM, Ali M, von Seidlein L, Kim DR, Hashim R, Reyburn R, Ley B, Thriemer K, Enwere G, Hutubessy R, Aguado MT, Kieny MP, Lopez AL, Wierzba TF, Ali SM, Saleh AA, Mukhopadhyay AK, Clemens J, Jiddawi MS, & Deen J (2012). Effectiveness of an oral cholera vaccine in Zanzibar: findings from a mass vaccination campaign and observational cohort study. The Lancet infectious diseases, 12, 837-844 PMID: 22954655

Further Reading:

1. WHO; Cholera. Link
2. Boustanshenas M, Bakhshi B, Ghorbani M. 2012 Oct 19. Investigation of immunological responses against a native recombinant CTB-whole cell Vibrio cholerae vaccine in a rabbit model.  Journal of Applied Microbiology. Link

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