Tag Archives: Vaccine

A little incentive goes a long way when it comes to vaccine uptake

Offering people free lentils and metal food dishes substantially improves the number of young children that receive a full course of childhood immunisations in resource poor areas, and is more cost effective than just improving the vaccine services available in the region, according to a new study published free in the British Medical Journal.

Abhijit Vinayak Banerjee and colleagues wanted to assess how effective non-financial incentives—1 kg raw lentils per vaccine and a set of metal thali plates once a child has received all their immunisations—and increased availability of vaccine services were at improving immunisation rates in young children in rural Rajasthan, India. Their study included 1,640 children (aged 1–3 years) from 134 villages who were randomly assigned to three groups:

-          the ‘immunisation camp’ who received reliable, monthly vaccinations from healthcare professionals

-          the ‘immunisation plus camp’ who in addition to reliable, monthly vaccines were also offered cheap little extras of free lentils (costing about $1) for every vaccine and a set of thalis (a snip at $1.50) for a complete set of vaccines (BCG, diphtheria-pertussis, tetanus, polio and measles) received by the children

-          a control group who did not receive any interventions

Taken from Banerjee, A. V. et al. BMJ 2010;340:c2220

The researchers showed that immunisation rates were higher in the children that were offered reliable immunisations plus a little extra (39%) compared with the rates in children who were just offered the reliable immunisations (16%). Interestingly, children in districts neighbouring the immunisation plus camp also had bigger improvements in immunisation rates than those living near the immunisation camp villages. Not only that, these small incentives were cost effective (costing an estimated $17.35 per fully immunised child in camps with incentives compared with $25.18 per fully immunised child in camps without these extras).

The findings from this study by Banerjee et al. could have important implications for vaccine policies. Moreover, the authors question whether offering lentils can even be considered a “cost” as they clearly will have immediate, nutritional benefits to both the vaccinated children and their families.

ResearchBlogging.orgBanerjee, A., Duflo, E., Glennerster, R., & Kothari, D. (2010). Improving immunisation coverage in rural India: clustered randomised controlled evaluation of immunisation campaigns with and without incentives BMJ, 340 (may17 1) DOI: 10.1136/bmj.c2220

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Vaccinate the kids to protect the “herd”

Vaccinating young children and adolescents against influenza protects unvaccinated individuals in the wider community (the herd immunity), show results from a clinical trial conducted in rural communities in Canada and published free in the journal JAMA. “Our findings … support selective influenza immunisation of school aged children with inactivated influenza vaccine to interrupt influenza transmission,” writes Mark Loeb and colleagues.

Influenza is an infectious disease which causes significant morbidity and mortality; in the United States around 36,000 people die, and 200,000 people are hospitalised, each year from influenza. Vaccination against seasonal and pandemic flu is fundamental to prevent the spread of disease. Current immunisation policy targets individuals who have a greater risk of flu complications, but flu vaccines can also be used to interrupt the spread of influenza across an entire population. Previous work has shown that children and adolescents play an important role in the transmission of influenza but it is still unclear whether vaccinating these children benefits the community as a whole and protects those that have not been immunised.

Loeb et al. recruited individuals from 46 Hutterite colonies in western Canada to test the community-wide benefits of flu vaccination programmes in children and young adolescents. Their cluster trial included 947 healthy children and adolescents, ranging from 3 to 15 years old, who they randomly assigned according to community to receive either a trivalent seasonal influenza vaccine or a hepatitis A vaccine as a control. They also recruited 2,326 members from the Hutterite communities who were not vaccinated during the study. All participants in the study were followed up for signs and symptoms of influenza over a six month period.

The investigators observed that the uptake of both vaccines in eligible healthy children was similar; 83% for the influenza vaccine and 79% for the hepatitis A vaccine. 119 unvaccinated individuals had laboratory-confirmed influenza; twice as many people in the communities assigned to the control vaccine had the disease compared to those communities assigned to influenza vaccine. Loeb et al. found that this pattern of disease incidence remained even when taking into account all study participants, including those who did and did not receive a vaccine. The researchers concluded that immunising children aged 3–15 years old against seasonal flu conferred 61% indirect protection in unvaccinated people.

“Our data suggest that a significant herd immunity effect can be achieved when the uptake of vaccine is approximately 80%,” write the investigators. Their study suggests that selectively immunising children during flu epidemics may help to prevent spread of the disease in the rest of the population.

ResearchBlogging.orgLoeb, M., Russell, M., Moss, L., Fonseca, K., Fox, J., Earn, D., Aoki, F., Horsman, G., Van Caeseele, P., Chokani, K., Vooght, M., Babiuk, L., Webby, R., & Walter, S. (2010). Effect of Influenza Vaccination of Children on Infection Rates in Hutterite Communities: A Randomized Trial JAMA: The Journal of the American Medical Association, 303 (10), 943-950 DOI: 10.1001/jama.2010.250

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M cells, gatekeepers or gateway to the gut

Glycoprotein 2 is the M cell receptor for type I pili on bacteria and is important for the immune response to these bacteria, according to research by Hase and colleagues published last week in the journal Nature.

The mucosal immune system is one of the largest components of our immune system and is hugely important for protecting mucosal surfaces (like our gastrointestinal tract) from harmful pathogens. Our guts are home to trillions of commensal bacteria which live quite happily there causing us no harm whatsoever. The gastrointestinal tract is protected from these bacteria (or other damaging substances) by a layer of tightly packed epithelial cells which form a barrier against any bacteria or molecules penetrating the gut. However, Microfold (M) cells are specialised intestinal cells located over mucosal lymphoid tissue called Peyer’s patches which are potential entry points into the host. M cells sample microorganisms or molecules in our gut and help transport them across the epithelial cell barrier (a process called antigen transcytosis) to deliver to professional immune cells (like macrophages, T cells or dendritic cells) to stimulate a protective immune response. In essence, M cells act like CCTV cameras to survey the gut area for anything that is out of the ordinary, or potentially harmful, and then present them to our immune system (essentially the police and the law courts) to sort those bad ‘uns out.

Previous work had shown that antigen transcytosis by M cells is important for mucosal immune responses but little was known about the mechanism involved. The researchers used microarray to scan the entire genome for specific molecules associated with M cells and found that glycoprotein 2 (GP2) was expressed in M cells in both human and mouse Peyer’s patches. Using immunoelectron microscopy they showed that GP2 was localised to the apical surface of M cells (the surface exposed to the commensal bacteria in the gut). Furthermore, they found that GP2 bound a variety of commensal and pathogenic enterobacteria (Escherichia coli, Salmonella enterica serovar Enteritidis and Salmonella Typhimurium), and more specifically bound to FimH expressed in the bacterial type I pilus (filamentous projections on the bacterial surface which are important for adhesion). Three-dimensional imaging revealed that GP2 accumulates around E. coli and S. Typhimurium as they are internalised in M cells and deletion of GP2 in mice reduced the uptake of type-I-piliated bacteria. After bacteria are translocated through M cells in a GP2-dependent manner they were captured by dendritic cells. Furthermore, GP2 was important for induction of mucosal immune responses against specific bacterial antigens (proteins that stimulate an immune response). Bacteria deficient in FimH lost the ability to bind GP2, had reduced entry into Peyer’s patches and induced a weak helper T cell and antibody immune response. Similarly, mice lacking GP2 had reduced helper T cell and antibody immune responses after challenge with bacteria expressing FimH.

This paper highlights the biological importance of GP2-dependent M cell antigen transcytosis as part of immunosurveillance in the intestine for bacteria expressing FimH. More work is needed to fully understand exactly what happens to the bacteria after they are delivered to immune cells and tissues by the M cells. Finally, M cells are thought to be a promising target for oral vaccinations to induce a protective immune response and this work shows that GP2 may be a possible vaccine target.

Although M cells act as a great surveillance system for the gut there are always a few bacteria that abuse the system. Shigella is one particular deviant bacterium that cannot normally invade the apical surface of intestinal epithelial cells and so uses the M cells to breach the epithelial cell barrier and gain access to their basolateral surface. Here, they can successfully invade, replicate in the intestinal epithelium, and wreak havoc on the gut by causing shigellosis or bacillary dysentery.

ResearchBlogging.org
Hase, K., Kawano, K., Nochi, T., Pontes, G., Fukuda, S., Ebisawa, M., Kadokura, K., Tobe, T., Fujimura, Y., Kawano, S., Yabashi, A., Waguri, S., Nakato, G., Kimura, S., Murakami, T., Iimura, M., Hamura, K., Fukuoka, S., Lowe, A., Itoh, K., Kiyono, H., & Ohno, H. (2009). Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response Nature, 462 (7270), 226-230 DOI: 10.1038/nature08529

Further reading

Jang, M.H. et al., (2004) Intestinal villous M cells: An antigen entry site in the mucosal epithelium. Proceedings of the National Academy of Sciences, 101, p.6110-6115.

Schroeder, G.N. and Hilbi, H. (2008) Molecular pathogenesis of Shigella spp.: Controlling host cell signalling, invasion and death by Type III secretion. Clinical Reviews Microbiology, 21, p.134-156.

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HIV vaccine trial not so positive after all

In September, scientists from the Thailand Ministry of Public Health, in collaboration with the U.S Army, hailed a breakthrough in research towards a HIV vaccine….a positive result. Now, the full results by Rerks-Ngarm and colleagues, published on 20th October in the New England Journal of Medicine, reveal that the outcome of the trial was not so positive after all…..in fact it was statistically insignificant (i.e. the results could have happened by chance).

 

Lab work 2The $105 million RV144 HIV/AIDS vaccine clinical trial included more than 16,400 volunteers aged 18 – 30 yrs old. Half were randomly picked to receive a combination of two HIV vaccines (ALVAC and AIDSVAX) whilst the rest received a placebo vaccine. The volunteers were monitored after a 6 month vaccination programme and every 6 months for a further 3 years. On the 24th September, the world media reported that the ALVAC-AIDSVAX combo was the first experimental vaccine to have a statistically significant effectiveness (~31%) at reducing the risk of HIV infection.

 

However, following the publication of the full analysis of the results last week the response from the scientific world has been somewhat muted. The scientists from the study themselves state that the results show only a “modest benefit” and reveal a 26% effectiveness at reducing the risk of HIV infection which was statistically insignificant (could have happened by chance). Also, the protective effects of the vaccine reduced after 12 months and the vaccine did not protect those at high risk of HIV infection (intravenous drug users and sex workers)

 

So how come there are two very different results within the same study? Basically, it is all down to which volunteers you include in the analysis of the results. The study started with 16,402 people who were randomly assigned to receive the vaccine or the placebo over the course of six months. However, 7 people were found to be already HIV-positive at the beginning and so were removed from the results. This meant that 8197 people received the HIV vaccine whilst 8198 received the placebo (16,395 total). During the course of the study, 2021 people were excluded from the results from the vaccine arm of the study and 1832 people were excluded from the results from placebo arm of the study. People were excluded for a number of reasons such as they were not given the full 6 doses of the vaccine during the course of the study, they were given the wrong dose of vaccine or were not given the vaccine in the correct time period. This meant that the final number of people that match all the experimental criteria for the study analysis was 6176 in the vaccine group and 6366 people in the placebo group (12,542 total).

 

The level of success of the vaccine depends on which set of people you pick to analyse:

  • the “modified intention to treat” set are the 16,395 people at the beginning of the trial (discounting the 7 people who were HIV-positive). Analysis of their results gives you the statistically significant 31% effectiveness of the vaccine
  • the “per protocol” set are the 12, 542 people at the end of the study who have received the correct dose and number of vaccines, and were HIV-negative during the course of the vaccination programme. Analysis of their results gives you the statistically insignificant 26% effectiveness of the vaccine.

 

The full results demonstrate just how difficult it is to interpret results from large clinical trials and the complexities in using statistical significance for confirming evidence-based research. The full analysis of the people who received the correct number of vaccines and the correct dose during the correct time period suggests that the ALVAC-AIDSVAX vaccine trial was not successful and more work is needed to find that elusive protective HIV vaccine.

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Researchers make first steps towards making a vaccine for urinary tract infections

utiFed up of stocking up on cranberry juice to stave off painful peeing….well researchers from the University of Michigan have made an important step towards making a vaccine to prevent urinary tract infections (UTIs), if the immunity seen in mice can be reproduced in humans. The findings by Alteri and colleagues were published this week in PLoS Pathogens (its open-access so go take a look at the paper for yourself).

UTI is a bacterial infection that affects any part of the urinary tract (including kidneys, ureter, bladder and urethra). They are incredibly common; it is thought 53% of women and 14% of men will experience a UTI during their lifetime. They are significant healthcare burden; in the United States alone, UTIs have an estimated annual cost of $2.4 billion each year. There are two types of UTI. Lower UTIs affect the bladder (cystitis) and urethra (urethritis) with symptoms of a mild fever, the urge to urinate frequently, smelly, bloody or cloudy urine, and that oh so infamous pain or burning sensation when you need to urinate. Upper UTIs affect the ureter and the kidneys (pyelonephritis) and include symptoms of high fever, nausea and vomiting, chills and shaking and localised pain in your lower back. Upper UTIs are potentially more serious since they can cause kidney damage. UTIs can be treated with antibiotics but there is increasing evidence of antibiotic resistance. Furthermore, recurrent infections occur frequently. An estimated 27% of women experience a second infection, and 2.7% of those suffer a third infection, within 6 months from the initial infection. Uropathogenic (pathogens that infect the urinary tract) Escherichia coli (UPEC) is the most likely cause of an uncomplicated UTI and so the researchers wanted to develop a vaccine to prevent infection by these bacteria.

The researchers used large-scale reverse vaccinology (pioneered by Rino Rappuoli and first used for vaccines against meningococci, the bacteria that cause meningitis). This combines bioinformatics, genomics and proteomics, to quickly and efficiently identify proteins in UPEC that are novel vaccine targets. The researchers looked for proteins to act as antigens, substances that would trigger an immune response to produce protective antibodies (a protein which binds foreign antigens to identify and neutralise them). The researchers screened 5,379 predicted bacterial proteins in the UPEC strain E. coli CFT073 and identified six proteins that matched vaccine candidate criteria including proteins that were highly expressed in vivo, specific to pathogens and induced during growth in human urine. The vaccine candidates were all pathogen-associated iron receptors (ChuA, Hma, Iha, IreA, IroN and IutA). These receptors are required for uptake of iron and are present on the surface of the bacteria. Each of the iron receptor proteins were expressed and purified and these antigens were cross-linked to cholera toxin, which acts as an adjuvant (a substance that increases the ability of an antigen to stimulate the immune system). Mice were inoculated with each antigen-adjuvant complex in their nasal passage. The researchers investigated whether mice could be protected from UTI and measured the immune response that occurred in the mice after vaccination.

Vaccination with Hma, IreA and IutA significantly protected mice against colonisation with UPEC strains in the kidneys and bladder. Spleen cells from vaccinated mice significantly secreted IFNγ and IL-17, which are protective proinflammatory cytokines (proteins released by cells which act as signalling molecules and help generate an immune response). Also, mice secrete protective antigen-specific antibodies following vaccination, which correlated with protection against infection with UPEC. Increased levels of IgA (an antibody found in mucous) were measured in urine and high levels of IgM (an antibody part of the primary immune response to a foreign antigen) and IgG (an antibody that is part of the secondary protective immune response) were measured in serum.

Vaccination with iron receptors elicits protective immunity from experimental UTI in mice. Iron receptors are promising vaccine candidates to protect against UPEC infections in humans and future clinical trials will determine whether the immunity seen here can be reproduced in humans. Interestingly, uptake of iron is a critical function required specifically by pathogenic bacteria in order to survive, but often not in commensal bacteria (normally harmless bacteria which are part of our natural microflora on and inside our bodies). Vaccines that include iron receptors could be used to prevent infections by other pathogenic bacteria. Also, the researchers show that vaccination in nasal mucous membranes induces an immune response in mucosal tissue elsewhere in the body, in this case the urinary tract. Although a successful UTI vaccine may be a long way off this paper details key research which should help its development.


Both these webpages give detailed info on symptoms, diagnosis and treatment of UTIs:

Medline Plus topic page on UTIs

http://www.nlm.nih.gov/medlineplus/urinarytractinfections.html

NHS direct topic page on UTIs

http://www.nhs.uk/conditions/Urinary-tract-infection-adults/Pages/Introduction.aspx

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