Why vaccine run is slower than the epidemic spread of virus?


Ebola under SEM (Courtesy: CDC)

Are we aware? What is happening? Where are the vaccines that proved to be successful? Why Ebola vaccines are still under trial? Why are there success stories been proposed in research papers? I am sure that these questions are must and most obvious. There are several reasons why a laboratory proposed vaccine needs long time to launch in market. Here in this small note brining you forward about why vaccines are slower than the epidemic run of virus.

While we take two names those come first are Zika and Ebola. Looking at Zika three vaccine candidates have proved to be successful in monkeys and another has reached under human trials. Unfortunately the run of Zika is much higher. It has already reached 66countries after Brazilian epidemic. On the other hand looking towards Ebola, two vaccines have reached its final trial. But Ebola had been reported to halt its spread since the last update on 10th of June with 28,616 cases and 11,310 deaths. (Read Ebola 2016 update on Biomysteries). So hopes are high but vaccine run is too slow and may be the Zika virus vaccines may take a year to reach the market.

So here are some reasons why vaccines are backlogging

  1. Before Epidemics

When disease starts to spread and often it takes late to understand what it is that is spreading high. So taking example of Zika which was known to spread in Brazil early August 2015, World Health Organization (WHO) reported its alarm in February 2016. In between Zika already has reached to be pandemic. For Ebola too, it took the same time to be understood what it is that spreading. Even investigators get affected with Ebola.

  1. Shifting strains

There are different strains every time. Common example would be Influenza which have multiple strains based on the protein coat Hemagglutinin (H) and Neuraminidase (N). So it is named on the type of strains like H1N1, H2N3, H1N4, etc. Similarly for Zika there are two strains African and Asian. The recent hit is considered to be similar to Asian strain. One of the scientific reason is low processivity of Viral DNA proofreads. So it may shift in between the strain. More it shifts slower would be the run for vaccine.

  1. Risky business for companies and lack of funds

It is not about the virus but about the vaccines. Big pharmaceutical companies can invest only for research and few come forward while there is an urgent need of vaccines. WHO also needs enough support of various companies to eradicate the Viral attack. The negative side lies when vaccines does not overcome all the clinical trials and make them push towards losses. So it is a big job for pharma companies to think before they invest. Whereas, WHO also lacks enough funding and it needs support so that all from the world can collaborate.

  1. Animal models

Once Scientists make a potential vaccine it has to be tested on rodents like rat or mice specifically. But sometimes it is not enough available to undergo testing. Also, it is not always that vaccines that worked on mice will work similarly on humans. The virus also may not affect rodent’s similar way as it does on humans. Although mice holds most genetic similarity with us but it is not same as humans.

  1. Reaching Human trials

It is the ultimate goal for any researchers to push the vaccine to human trials. It is not always to take lightly but there are many vaccines that made it to human trials. Unfortunately the bad news is companies struggle to find enough volunteers to continue the trials.


It is just a brief story about the hurdles that most vaccines need to face. The morale of the story is although the epidemic spread runs like rabbit but the race is finally for vaccines although it runs like turtle. It needs enough support to build the bridge between the clinical trials. Scientists, organizations and companies are equally struggling to halt the spread of Zika with successful vaccine. Hope the final news hits soon.

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NorA Multidrug resistance Efflux pumps in Staphylococcus aureus

Gram positive organisms can be resistant to first line of antimicrobial agents and leading to complications in therapy. One of major reasons for these complications is efflux pumps. Apart from Drug resistance efflux pumps are used by bacteria to acquire nutrients, establish proper membrane charge and pH gradient, and to excrete out the by-products. [1] The efflux pumps are natural process that allows bacterial survival against multiple environmental challenges. There are lots of potential researches about gram positive efflux pumps and amongst those norA is much notable pump to be discussed here.

Types of efflux pumps

Efflux pumps in Gram positive bacteria are encoded by both plasmid and/or chromosomally expressed genes. For transmissible drug-specific efflux pumps are encoded by plasmids, whereas those which are multidrug resistance (MDR) are usually encoded by chromosome and not donated to other organisms. The plasmid based efflux pumps are multi copy in nature without any additional need of subsequent mutations. On the other hand, MDR occurs due to increased gene expression or occurrence of regulatory mutations.

Types of Efflux pumps in S aureus

Image: Multidrug efflux pumps in S. aureus which is categorized into four families of proteins: major facilitator super-family (MFS), the ATP-binding cassette (ABC) superfamily, the multidrug and toxin extrusion (MATE) family,and the small multidrug resistance (SMR) family.

NorA efflux pump

NorA was first identified efflux pump which is encoded by Staphylococcus aureus. As it is encoded by chromosome and can be well categorized under Multidrug resistance Efflux pumps. The function was identified when norA gene was cloned from the chromosome and based on its nucleotide sequence it was identified to encode major facilitator superfamily protein with 12 transmembrane segments.  NorA efflux pump is amongst the 8efflux pumps known. The others are NorB, NorC, MdeA, LmrS, SdrM, QacA and QacB efflux pumps. Check Figure for the classes of MDR efflux pumps in S. aureus.

Although the function was unknown until Yu et al in 2002 inhibited the protein motif force (pmf) that was necessary for norA gene to function. [3] Most of the active research was in the study of regulation. Most active regulators known are MgrA, NorR and NorG. MgrA fine tune the expression of norA gene and also norB gene and relates with the phophorylation status of the gene. NorG, a GntR-like regulatory protein found to bind the promoter of norA gene. Interestingly, disruption of norG does not affect the transcript of norA rather it provides susceptibility of S. aureus toward beta-lactam antibiotics. Thus norG has additional functions too apart from regulation of norA.

norA is highly expressed in MRSA isolates along with norB genes. Several researches have been experimented on detail role of this efflux pump and notably the promoter regulation of this gene. This is just an overview of one of the efflux pumps but there are more to this and research disclosed several pattern to disrupt the mechanism. Unfortunately there are way other mechanisms S. aureus bring forward for resistance.

Find the following video of a brief about of efflux pump

Additional Reading:

  1. Jang S. 2016. Multidrug efflux pumps in Staphylococcus aureus and their clinical implications. Journal of Microibology 54(1): 1-8
  2. Schindler, B.D; Kaatz, G.W 2016 Multidrug efflux pumps of Gram-positive bacteria. Drug Resistance Updates 27: 1-13
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Interview of Dr. Prashanth Suravajhala

Dr. Prashath Suravajhala made his recent visit in India and I am glad that he welcomed me and spent some time for a scientific interview in between at Ecological Park, Kolkata, India. Dr. Partha Sarathi Das also joined, who is a post doctoral researcher at Vidyasagar University.

Prash shared about his current research, his thoughts on current teaching process, bioinformatics research and also about Bioclues Organization as how he framed it.

Find the full interview here. The weather was windy and even in scorching he heat he didn’t complain.

Click CC after you play the video to get the subtitle.


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Interview of Dr. Partha Sarathi Das from Vidyasagar University

It was a general meet of scientists at a common place called Ecological Park (commonly known as Eco park) at Kolkata, India where I am glad to meet Dr. Partha Sarathi Das. It was a common welcome from Dr. Prashanth Suravajhala (Post Doctoral Scientist from Aarhus University, Denmark) for his scientific visit at Kolkata.

I am glad that I shared the screen on behalf of Bioclues Organization with Dr. Das sharing his thoughts over recent advancements in Bioinformatics research in India, share his research and also how to uplift thoughts and research processes in Bioinformatics.

Please click CC after playing the video.

Although it was windy and scorching heat, but still he shared his views without complain. Great man indeed.

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Where is Ebola now? 2016 update


Colorful Ebola under Transmission Electron Microscope (Image: CDC)

The Deadlier Ebola outbreak and it was one of the major pandemic known. This small neither living nor dead nanoscale object shook the world back in 2013-2014 and also after. It was a mighty fight among the researchers around the globe to bring down this Ebola virus (EBOV) outbreak. Thousands of research took place and organizations from different countries came hand to hand with World Health Organization (WHO) for immediate action. It wasn’t been easy then since multiple research does brought some light to cure but they need to go through some controversies. I published a science communication review back in 2015 under International Journal of Microbiology and Allied Sciences along with Mr. Sagar Aryal (Science Blogger at Microbiology World, Nepal) and Dr. Aftab Ahmad (President at National Academy of Young Scientists, Pakistan) highlighting the controversies and solutions 2015. Here I am highlighting the current scenario upto 8th of July 2016.


Image: WHO

Ebola hit 2013-2015 (based on the paper Ebola outbreak controversies and solutions 2015)

Let’s rewind back in December 2013, WHO confirms on 30th with 27,049 cases at three major hit centres – Liberia, Guinea and Sierra Leone. Then soon from these three major states it starting to spread to other parts of Africa, Europe and even found cases in United States. EBOV spreads from fruit bats especially some species found in Africa. It was believed that the spread was due to consumption of bat as food. The fatality rate was too high (41.02%) and was rising exponentially. All turned to WHO for answers and WHO itself was muddled. Researchers and Companies all around the globe united to accept this challenge and successfully came with multiple possible vaccines that does work in animal models. But the controversies struck then when it comes to human trial. WHO was under huge burden of financial crisis as the budget was much higher than they require.

Check the documentary of the 2013-2015 outbreak

It was 24th of October with 10,141 confirmed cases and 4,922 deaths. Researchers from Yale University had predicted that if there are no better measures taken then it will take a record rise by mid of November 2014. Unfortunately the prediction followed and still researchers were arguing with their researched vaccines proposed still tied in the knots of controversy. With some vaccines like ZMapp (the triple antibody), GSK proposed vaccines, etc the steep rise was getting submerged now. The Nigerian government has quarantined the whole country to prevent any further spread. But EBOV does not obey such rule and it was spreading. Many scientists who were working even got affected with EBOV.

WHO still was fighting strong with much collaboration to eradicate EBOV completely. The review was written up to WHO’s report of 10th June 2015. Surprisingly the record has reached more with 27,237 confirmed cases and 11,173 deaths. It was not restricted to African countries and it had become glober concern of fear of EBOV with positive cases found in US, UK, Senegal, Spain and Italy.

Ebola 2016 update

After all these steep rise and fear of EBOV, where is it now? Are we free from the risk of EBOV completely? In the 9th of June WHO’s last update till now declares the end of EBOV outbreak in Liberia. The announcement was done after surveillance for 42days post to last confirmed Ebola patient who was tested negative for second time. Still Liberia is now under 90days trial of strict surveillance. (Read the WHO’s last press of 9th June here)

According to the final update till now there are 28,616 cases and 11,310 deaths (check the data here) as on 10th of June 2016. So how does this total expedition of hunting EBOV coming to an end? What are the vaccines those come out of the controversial trial and made success?

It is important to note that there is not yet any final vaccine for EBOV. Ebola keeps on mutating itself and change its strain. Most of the vaccines that might work on some, may not work for others. A British company GlaxoSmithKline developed a vaccine ChAd3-ZEBOV that had made to final trial during Ebola Outbreak and another from Merck, a company from US. Governments from each national took step to prevent further spread of Ebola. A combined effect may have provided a huge success to stop this outbreak. The recovery was known for some people used the trial vaccines to save their life but also some have not recovered. WHO and World Economic Forum now are having more conversation with these companies to provide possible vaccines into human trial in future to confirm the application.

Suggested readings:

  1. The Ebola outbreak is over, but the hunt for a vaccine continues. Michell Eloy, February 25, 2016. Marketplace dot org
  2. Looking, hopefully, towards an Ebola-free future. April 2016, WHO.
  3. Ebola virus disease outbreak. (total news by WHO)
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Global emergency of Polio from Hyderabad, India

On 14th of June Talengana government announced ‘global emergency’ after an active strain of wild polio virus (P2 strain) was detected in water sample collected from a drain at Ranga district.


Image Courtesy: Times of India representative

The vaccine derived polio virus (VDPV) strain has not been seen in the country for long (around 5 years).  It has also been reported to be safe as no such positive cases been detected although the regional government wish to alarm emergency to avoid reach to neighbouring countries as well as in India. The government soon going to launch massive vaccination programme before it become pandemic.

Earlier the oral polio vaccination contained attenuated P1, P2 and P3 strains but as P2 strain not been communicated so far, the recent vaccines lack P2 strain. “In this case, the P2 strain is vaccine derived. Someone vaccinated 10 months to a year back released the strain through stool. Such rare cases happen when a child’s immunity is very low. To avoid such stray cases, that happens one in a million, the P2 strain is no longer given even in vaccines,” said Dr G Srinivasa Rao, chief programme officer, National Health Mission, Telangana was said to Times of India.

“We’ll be following WHO set standards during our programmes,” he added. As part of the special campaign, children aged between six weeks to three years will be given additional doses of the injectable polio vaccine (IPV). Booths will be set up in areas being covered in these campaigns.

Officials informed that they will not deploy teams for door to door vaccination rather will encourage people to bring their children at vaccine booth which will provide additional information and protection against all kinds of polio strains.

Source: Times of India

Additional reading: History of Polio Vaccination, WHO’s report on India’s Polio status, Polio virus wiki study

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Yoshinori Ohsumi wins 2016 Paul Janssen Award

Japanese scientist and professor Ohsumi from Tokyo Tech has been recognized for his research in autophagy.


Dr. Yoshinori Ohsumi (Courtesy: Asian Scientist Newsroom)

From the AsianScientist newsroom on 14th  2016 its been known that Dr. Yoshinori Ohsumi, professor at Cell Biology Unit at Tokyo Institute of Technology is the recipient of this year (2016) Dr. Paul Janssen Award for biomedical research. This was confirmed last week in Biotechnology Industry Organization convention in San Francisco, California.

He was awarded in honour of his work as an active scientist in academia with his transformational contribution towards improvement of human health. Dr. Ohsumi’s research can be found at his research gate profile. He is well known for his discoveries relating to molecular mechanisms of autophagy, a process by which the cell degrades their own structures.

From his quote “As a basic biologist, I started autophagy research 27 years ago aiming to elucidate the functions and mechanisms of the cell at the molecular level. From the beginning, I never expected that my research would spread to medical fields or to drug discovery technology. So I am very surprised to have been selected for this award. However, I am pleased and grateful to have this fundamental work be recognized as important even in the medical and pharmaceutical fields.”

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NCBI PubMed Filter

Researchers often search research papers based on their interest and currently they study. Among many research databases PubMed of NCBI is one of the important priority. PubMed stores access of many journal abstracts and direct links to the journal. I recently uploaded a small video under We The Microbiologist, India ‘s Bio-Blog about how to use filters to search your relevant papers.

It is important for researchers to search for particular author, particular organism, some specific title, year, journal and more based on their choices. I hope the above video will help many researchers as well as students.

Happy Learning.

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“I will forever persist” – the unsaid words of Persister cells

Persister cells are antibiotic tolerant cells which can be identified in almost all phases of bacterial cellular growth with antibiotic tolerance. It holds many unfold mysteries of in biofilm resistance. They are not mutants, rather phenotypic wild type variants and the reduced metabolic rate makes them distinguishable. The extensive research behind the mechanism has identified many persister genes and the reason behind the non-dividing state of these cells. The article here discuss over why persister cells persist any invasion on them.

Before we look into some researches it is better to provide a brief introduction about how persister cells develop. There are two types of persister cells based on the intracellular and environmental stress.


Type1 and Type2 persister cells (Credit:Microbe Wiki)

Type 1: These cells develop persistence in stationary phase when nutrients are low enough for numerous cell growths. Bacteria are known to sense these stressful conditions and allow them to push some of their population to be dormant, while rest thrive and risk death. These dormant cells are antibiotic tolerant and starve to live without enough nutrition.

Type 2: These cells believed to be evolved from prolonged antibiotic stress and often some stress imposed by prophages. These cells are not triggered by environment and are slow growing.

Why can’t we stop persister cells?

Dr. Kim Lewis from North-Eastern University unleashes a gene which fakes the action of antibiotics to prevent the growth of biofilm. In year 2004, the research published in Journal of Bacteriology explained about HipA gene which generates a toxin named RelE that allows the persister cells to hibernate. As antibiotics must work on metabolically active growing cells hence outlasting the antibiotic activity then repopulates the infection.

A question does arise about how these persister cells maintain their persistence. The answer was revealed in late 2015, a research published in PNAS about a toxin called HigB that able to recognize and rips up RNA to allow growth inhibition function. Although it does not degrade all RNAs equally under stress, it is exquisitely selective. X-ray crystallography studies reveal the exact mechanism how HigB recognizes mRNA and then interacts with ribosomes. The protein was investigated in the bacterium Proteus vulgaris a potent contender of urinary tract infection.

Efforts were done to further understand and visualize the persister mechanism of cells. A year before, i.e. in 2014 researchers from Imperial College of London publishes a research in journal Science , where they describe the mechanism of forming persisters inside macrophages. They fluorescently labelled protein which is produced inside bacterium Salmonella and found that some group of bacteria form persister cells by rendering their growth while remaining follows normal growth. The phenomenon was observed after macrophages engulfed the bacterium. Thus helping bacterium to survive the antibiotics treated.

Door for success behind impossibility

Researchers were almost confused and tried to open doors of possibility to defeat the hidden troops of bacteria called persisters. It was not impossible but to find out a way was difficult. Yet there are some researches which unwrapped the possibilities.

Researchers from Scripps Research Institute, Howard Huges Medical Institute and Albert Einstein College of Medicine of Yeshiva University came up with promising anti-tuberculosis compound which is able to attack both active and dormant Tuberculosis bacterium. After screening diverse library of compounds they found TCA1 capable to kill 99.9% of the activated replicating TB bacterium. But with combination with Isoniazid or Rifampin is 100% effective in any TB bacterium. Positive shade of the experiment was received after thorough experiment over mice and no adverse side effects were found. The research was published in 2013 in PNAS.

In 2015, Northeastern University researchers described a method called pulse dosing. Their findings were published in the journal Nature where they identify toxin-antitoxin gene pairs which maintain the persister cells. These gene pairs encode proteins called HipA (for toxin) and HipB (for antitoxin) where they can regulate each other to module the functioning of the persister mechanism. It is also found that mutation in gene of HipA allow more persisters to form. Researchers came forward with a mechanism called pulse dosing, where antibiotics are provided at intervals. Post antibiotic treatment initially makes the cells to form persister but as they rise up again another antibiotic treatment is followed.


There are lot of strategies which have followed by researchers but still there are certain gaps behind understanding the mechanism of persister cells that remain vague. Bacteria always follow a cell to cell communication which allows them to collect nutrients and also response to danger. The collective evolution of genetic makeup that bacteria posses with environmental stress made them to modify. We can say the result of one such type of modification is persister cells. They do not posses antibiotic resistance gene yet they are resistant to antibiotic treatment. They do not grow yet they are alive. Persister cells research is now a rising calamity among microbiologists to identify cure against this evil. Yet it is magical to understand that these tiny creatures developed themselves strategies to escape their eradication.

Further Reading

  1. Northeastern University. “New Study Discovers Why ‘Persister’ Cells Never Say Die.” ScienceDaily. ScienceDaily, 15 December 2004.
  2. Marc A. Schureck, Jack A. Dunkle, Tatsuya Maehigashi, Stacey J. Miles, Christine M. Dunham.Defining the mRNA recognition signature of a bacterial toxin protein. PNAS, 2015.
  3. Helaine, A. M. Cheverton, K. G. Watson, L. M. Faure, S. A. Matthews, D. W. Holden.Internalization of Salmonella by Macrophages Induces Formation of Nonreplicating PersistersScience, 2014; 343 (6167): 204
  4. Feng Wang, Dhinakaran Sambandan, Rajkumar Halder, Jianing Wang, Sarah M. Batt, Brian Weinrick, Insha Ahmad, Pengyu Yang, Yong Zhang, John Kim, Morad Hassani, Stanislav Huszar, Claudia Trefzer, Zhenkun Ma, Takushi Kaneko, Khisi E. Mdluli, Scott Franzblau, Arnab K. Chatterjee, Kai Johnson, Katarina Mikusova, Gurdyal S. Besra, Klaus Fütterer, William R. Jacobs, Jr., and Peter G. Schultz.Identification of a small molecule with activity against drug-resistant and persistent tuberculosisPNAS, 2013
  5. Maria A. Schumacher, Pooja Balani, Jungki Min, Naga Babu Chinnam, Sonja Hansen, Marin Vulić, Kim Lewis, Richard G. Brennan.HipBA–promoter structures reveal the basis of heritable multidrug tolerance. Nature, 2015.


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Resistance of bacteria from stomach acid with the power of Intimin

Most of the bacteria usually communicate our body’s inner mechanism by mouth and nose, which are regarded as the most common entry. Many people get diarrhoea when some of these bacteria which have entered become opportunistic. One of the most common is E. coli. These bacteria can able to attach themselves on the walls of the intestines and inject toxins which allow us to fall sick. But one thing which might be missing in between is that, these bacteria which follow their entry into digestive system should get killed by strong acid present in stomach, which we know as a strong barrier of infection.

A research group from “The Bacterial Cell Envelope” research centre at University of Tübingen with Tübingen University Hospitals, investigated the phenomenon how gut bacteria survives the strong acid of stomach to enter into intestines. The results were published in the journal Molecular Microbiology.

Commonly, E. coli and Yersinia are found in small intestines and absorb nutrients. A protein named as intimin (named after intimate adherence) which allows the bacterium to adhere to the intestinal walls. It also form tiny channels between the bacterial wall and the intestinal cells to allow the toxins (causing diarrhoea) to move into intestines.

Intimins are autotransporters and are important virulence factors of both E. coli and Yersinia spp. These proteins have lysin motif which allows the binding with the peptidoglycan. This binding is possible only in acidic conditions, which clearly displays the reason how these bacteria uses the stomach acid for getting resistance. The intimin gets inserted then into the bacterial envelope thus stabilizing the structure of peptidoglycan.

Scientists conclude that intimin supports infection process in intestine, using the stomach acid boosting the bacterial virulence.

Research Source:

Jack C. Leo, Philipp Oberhettinger, Manish Chaubey, Monika Schütz, Daniel Kühner, Ute Bertsche, Heinz Schwarz, Friedrich Götz, Ingo B. Autenrieth, Murray Coles, Dirk Linke: “The Intimin periplasmic domain mediates dimerisation and binding to peptidoglycan.” Molecular Microbiology, DOI:10.1111/mmi.12840

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