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Polio could be wiped out in Nigeria, one of the last blackspots for the disease, thanks to an improved vaccine. A recently introduced polio jab is four times more effective at protecting children than previous vaccines and could eradicate type 1 polio – the most common form in Nigeria – if it reaches enough children.

Effectiveness of Immunization against Paralytic Poliomyelitis in Nigeria. 2008 NEJM 359: 1666-1674
The number of cases of paralytic poliomyelitis has declined in Nigeria since the introduction of newly licensed monovalent oral poliovirus vaccines and new techniques of vaccine delivery. Understanding the relative contribution of these vaccines and the improved coverage to the decline in incident cases is essential for future planning. We estimated the field efficacies of monovalent type 1 oral poliovirus vaccine and trivalent oral poliovirus vaccine, using the reported number of doses received by people with poliomyelitis and by matched controls as identified in Nigeria’s national surveillance database, in which 27,379 cases of acute flaccid paralysis were recorded between 2001 and 2007. Our estimates of vaccine coverage and vaccine-induced immunity were based on the number of doses received by children listed in the database who had paralysis that was not caused by poliovirus. The estimated efficacies per dose of monovalent type 1 oral poliovirus vaccine and trivalent oral poliovirus vaccine against type 1 paralytic poliomyelitis were 67% and 16% respectively and the estimated efficacy per dose of trivalent oral poliovirus vaccine against type 3 paralytic poliomyelitis was 18%. In the northwestern region of Nigeria, which reported the majority of cases during the study period, coverage with at least one dose of vaccine increased from 59 to 78%. Between 2005 and 2007, vaccine-induced immunity levels among children under the age of 5 years more than doubled, to 56%. The higher efficacy of monovalent type 1 oral poliovirus vaccine (four times as effective as trivalent oral poliovirus vaccine) and the moderate gains in coverage dramatically increased vaccine-induced immunity against serotype 1 in northern Nigeria. Further increases in coverage in Nigerian states with infected populations are required to achieve the levels of vaccine-induced immunity associated with the sustained elimination achieved in other parts of the country.

Related:

• Vaccination against polio should not be stopped
• Epidemics to eradication: the modern history of poliomyelitis

The discovery of a previously unknown mechanism of immunity may lead to a better way to protect vulnerable children and adults against Streptococcus pneumoniae (pneumococcus) infection. The findings may aid the development of novel pneumococcal vaccines that would be less expensive and cover a greater number of known pneumococcal strains than that currently available. Pneumococcus causes serious infections in children and the elderly, including pneumonia and meningitis (inflammation of the brain). Since 2000, U.S. infants have been routinely immunized against pneumococcus, but most developing countries (where nearly one million children die from pneumococcal infections annually) cannot afford the existing vaccine. Researchers have been studying how natural immunity against pneumococcus develops, and have shown that in addition to antibodies, T-cells can provide broad protection against this pathogen. This new study identifies the specific protective T-cells – so-called T_H17 cells – and show that they protect against infection by releasing IL-17, a protein that enables human blood cells to kill pneumococcus in the nose more efficiently. This is significant, since colonizing a person’s nose is the first necessary step of infection. Researchers knew that as children get older, they carry pneumococcus in the nose for shorter periods of time and have less risk of disease, but it hadn’t been known how this resistance develops. This works shows that adults and older children, but not newborn babies, have T_H17 cells that target pneumococci, suggesting that exposure to pneumococcus normally leads to production of these cells. In mice, they show directly that exposure to pneumococcus triggers the development of these T cells and shortens the duration of nasal carriage of the pathogen. The investigators also describe an efficient way of measuring T_H17 cells, which could help determine whether a new vaccine is rallying an effective response. A vaccine that induces both protective antibodies and T-cell immunity to pneumococcus may be a very effective way to protect against this potentially devastating disease.

Interleukin-17A Mediates Acquired Immunity to Pneumococcal Colonization. 2008 PLoS Pathog 4(9): e1000159
Although anticapsular antibodies confer serotype-specific immunity to pneumococci, children increase their ability to clear colonization before these antibodies appear, suggesting involvement of other mechanisms. We previously reported that intranasal immunization of mice with pneumococci confers CD4+ T cell–dependent, antibody- and serotype-independent protection against colonization. Here we show that this immunity, rather than preventing initiation of carriage, accelerates clearance over several days, accompanied by neutrophilic infiltration of the nasopharyngeal mucosa. Adoptive transfer of immune CD4+ T cells was sufficient to confer immunity to naïve RAG1-/- mice. A critical role of interleukin (IL)-17A was demonstrated: mice lacking interferon-gamma or IL-4 were protected, but not mice lacking IL-17A receptor or mice with neutrophil depletion. In vitro expression of IL-17A in response to pneumococci was assayed: lymphoid tissue from vaccinated mice expressed significantly more IL-17A than controls, and IL-17A expression from peripheral blood samples from immunized mice predicted protection in vivo. IL-17A was elicited by pneumococcal stimulation of tonsillar cells of children or adult blood but not cord blood. IL-17A increased pneumococcal killing by human neutrophils both in the absence and in the presence of antibodies and complement. We conclude that IL-17A mediates pneumococcal immunity in mice and probably in humans; its elicitation in vitro could help in the development of candidate pneumococcal vaccines.

Related:

• Pneumococcus: the quorum-sensing killer
• Bugs in space
• Vaccination is up to 99% effective

Background: The presence of measles virus (MV) RNA in bowel tissue from children with autism spectrum disorders (ASD) and gastrointestinal (GI) disturbances was reported in 1998. Subsequent investigations found no associations between MV exposure and ASD but did not test for the presence of MV RNA in bowel or focus on children with ASD and GI disturbances. Failure to replicate the original study design may contribute to continued public concern with respect to the safety of the measles, mumps, and rubella (MMR) vaccine.
Methodology/Principal Findings: The objective of this case-control study was to determine whether children with GI disturbances and autism are more likely than children with GI disturbances alone to have MV RNA and/or inflammation in bowel tissues and if autism and/or GI episode onset relate temporally to receipt of MMR. The sample was an age-matched group of US children undergoing clinically-indicated ileocolonoscopy. Ileal and cecal tissues from 25 children with autism and GI disturbances and 13 children with GI disturbances alone (controls) were evaluated by real-time reverse transcription (RT)-PCR for presence of MV RNA in three laboratories blinded to diagnosis, including one wherein the original findings suggesting a link between MV and ASD were reported. The temporal order of onset of GI episodes and autism relative to timing of MMR administration was examined. We found no differences between case and control groups in the presence of MV RNA in ileum and cecum. Results were consistent across the three laboratory sites. GI symptom and autism onset were unrelated to MMR timing. Eighty-eight percent of ASD cases had behavioral regression.
Conclusions/Significance: This study provides strong evidence against association of autism with persistent MV RNA in the GI tract or MMR exposure. Autism with GI disturbances is associated with elevated rates of regression in language or other skills and may represent an endophenotype distinct from other ASD.

Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A Case-Control Study. 2008 PLoS ONE, 3 (9) doi:10.1371/journal.pone.0003140

Related:

• MMR: our children, our choice?
• Measles and Mumps in the USA

There has recently been an upsurge of measles cases in the United States, mostly because of parents misguided fears of vaccinations. In the first seven months of this year, 131 cases were reported to the Centers for Disease Control, more than during the same period in any year since 1996. No deaths were reported, but at least 15 patients were hospitalized.

At the same time:

Recent Resurgence of Mumps in the United States. N Engl J Med. 2008 358: 1580-1589
The widespread use of a second dose of mumps vaccine among U.S. schoolchildren beginning in 1990 was followed by historically low reports of mumps cases. A 2010 elimination goal was established, but in 2006 the largest mumps outbreak in two decades occurred in the United States. Researchers examined national data on mumps cases reported during 2006, detailed case data from the most highly affected states, and vaccination-coverage data from three nationwide surveys. A total of 6584 cases of mumps were reported in 2006, with 76% occurring between March and May. There were 85 hospitalizations, but no deaths were reported; 85% of patients lived in eight contiguous midwestern states. The national incidence of mumps was 2.2 per 100,000, with the highest incidence among persons 18 to 24 years of age (an incidence 3.7 times that of all other age groups combined). In a subgroup analysis, 83% of these patients reported current college attendance. Among patients in eight highly affected states with known vaccination status, 63% overall and 84% between the ages of 18 and 24 years had received two doses of mumps vaccine. For the 12 years preceding the outbreak, national coverage of one-dose mumps vaccination among preschoolers was 89% or more nationwide and 86% or more in highly affected states. In 2006, the national two-dose coverage among adolescents was 87%, the highest in U.S. history. Despite a high coverage rate with two doses of mumps-containing vaccine, a large mumps outbreak occurred, characterized by two-dose vaccine failure, particularly among midwestern college-age adults who probably received the second dose as schoolchildren. A more effective mumps vaccine or changes in vaccine policy may be needed to avert future outbreaks and achieve the elimination of mumps.

Related:

• Vaccination is up to 99% effective
• MMR: our children, our choice?
• Virus infection during childhood linked to psychosis
• How Measles Virus Infects Cells
• Negative sense RNA viruses

Resistance to ciprofloxacin, a member of one of the most commonly used groups of antibiotics in the world, has been discovered by a team of Canadian researchers among people in remote South American villages who are believed to have never taken this medication. The researchers found high levels of ciprofloxacin resistance in Escherichia coli in Amerindians from the Guyanese rainforest. These individuals are reported as never having received treatment with ciprofloxacin or related fluoroquinolone antibiotics. The Amerindians had however received frequent treatment for malaria (which is a eukaryotic parasite and not a bacterium) with chloroquine. Chloroquine is used widely around the world to combat malaria, and it also is a close chemical cousin of the fluoroquinolones. Fluoroquinolones began widespread use in the late 1980s and now are among the most commonly used antibiotics in North America and Europe. Because the bacteria carried by the Guyanese Amerindians were resistant to ciprofloxacin, the researchers suggest that it is possible that exposure to chloroquine may make the bacteria that people carry in their intestines resistant to fluoroquinolones – a theory that, if corroborated by further research, could have important public health implications in developing countries and in the developed world. They also found resistance in many other species of bacteria – including Salmonella – that are found in rectal swabs. This means that chloroquine use for malaria may make the fluoroquinolones less effective for many common tropical diseases such as typhoid fever, diarrheal illnesses, and possibly also tuberculosis and pneumonia in the developing world.

Plans are being considered by major global health-promotion organizations to launch a campaign of widespread use in Africa and South America of a new anti-malarial treatment regimen called Artemesinin combination therapy (ACT). ACT usually includes quinoline drugs similar to chloroquine. These drugs are closely related to both chloroquine and fluoroquinolones. The researchers plan to carry out further studies to identify whether some quinolines may be less likely to induce quinolone resistance than others, and thus may be safer for malaria control programs. Dr Mike Silverman and 19 other volunteer health care professionals traveled by airplane from Bartica, a town that serves as the gateway to the interior of the Guyanese rainforest, to a handful of remote villages as part of annual humanitarian medical missions between 2002 and 2005. They took rectal swabs from 535 people in Bartica and the remote villages. They also asked the local inhabitants about whether they had ever been exposed to chloroquine or fluoroquinolones, and took water samples. They took the samples home and analyzed them. The team found that 5.4% of the rectal-swab samples contained ciprofloxacin-resistant Escherichia coli, with a 4.8% resistance rate among the remote-village samples. This is a very high rate – particularly when compared to the 4% rate found in a recent study of ciprofloxacin resistance in American intensive care units where fluroquinolones are very intensively used. It is also particularly remarkable because fluoroquinolones had never been available in these communities.

The ciprofloxacin-resistant E. coli samples were also all found to be highly resistant to chloroquine, and to have characteristics that would confer resistance to all fluoroquinolones including the newer drugs levofloxacin and moxifloxacin. Furthermore, the team found that one of the water samples they took in 2004 contained ciprofloxacin-resistant E. coli and another contained a small amount of chloroquine, probably from human waste contamination. Because of a widespread malaria outbreak in rural Guyana in late 2002, 30% of the villagers tested by the Canadian team in 2003 said they had been given chloroquine within the past six months, and in 2005 86% said they had used chloroquine within the past two years. The rates of chloroquine use may in fact have been much higher the investigators believe. This is because patient reports are not always reliable, and because of the very extensive treatment with chloroquine during the late-2002 malaria epidemic. The data also showed that community-wide fluoroquinolone resistance rose dramatically shortly after the malaria outbreak, further suggesting a link between chloroquine use for malaria and bacterial resistance to fluoroquinolones. Together, these data suggest that we must focus our efforts on prevention of malaria using mosquito-control measures such as bednets and by developing vaccines. For the short term, however, we still will have no choice but to use these lifesaving antimalarial drugs. However we need to investigate which of the antimalarials can be used in the future with the least impact on bacterial drug resistance.

Antimalarial Therapy Selection for Quinolone Resistance among Escherichia coli in the Absence of Quinolone Exposure, in Tropical South America. PLoS ONE 3(7): e2727
Bacterial resistance to antibiotics is thought to develop only in the presence of antibiotic pressure. Here we show evidence to suggest that fluoroquinolone resistance in Escherichia coli has developed in the absence of fluoroquinolone use. Over 4 years, outreach clinic attendees in one moderately remote and five very remote villages in rural Guyana were surveyed for the presence of rectal carriage of ciprofloxacin-resistant Gram-negative bacilli (GNB). Drinking water was tested for the presence of resistant GNB by culture, and the presence of antibacterial agents and chloroquine by HPLC. The development of ciprofloxacin resistance in E. coli was examined after serial exposure to chloroquine. Patient and laboratory isolates of E. coli resistant to ciprofloxacin were assessed by PCR-sequencing for quinolone-resistance-determining-region (QRDR) mutations. In the very remote villages, 4.8% of patients carried ciprofloxacin-resistant E. coli with QRDR mutations despite no local availability of quinolones. However, there had been extensive local use of chloroquine, with higher prevalence of resistance seen in the villages shortly after a Plasmodium vivax epidemic (p 0.01). Antibacterial agents were not found in the drinking water, but chloroquine was demonstrated to be present. Chloroquine was found to inhibit the growth of E. coli in vitro. Replica plating demonstrated that 2-step QRDR mutations could be induced in E. coli in response to chloroquine. In these remote communities, the heavy use of chloroquine to treat malaria likely selected for ciprofloxacin resistance in E. coli. This may be an important public health problem in malarious areas.

Northern Nigeria is currently affected by a new outbreak of wild poliovirus type 1 (WPV1), which has begun to spread internationally. In 2008, a nine-fold increase in new cases caused by this serotype has been reported compared with the same period in 2007. This outbreak in northern Nigeria has the potential to cause major international outbreaks, as occurred in 2003-2006. This year, Nigeria accounts for 86% of WPV1 cases in the world.

W.H.O.

Related:

• Vaccination against polio should not be stopped
• Vaccine-Derived Polioviruses
• Epidemics to eradication: the modern history of poliomyelitis

In the years during and after World War II, the Microbiological Research Establishment (MRE) at Porton Down was the UK Government’s centre for germ warfare research (or defence, depending on who you believe). There were two parts to the MRE, the part “outside the wire”, which contained among other things, the Common Cold Unit, and the section “inside the wire”, which was top secret and has been the subject of much rumour and speculation.

I recently came across an article by Bill Parker, who worked at the MRE for two years and which lifts some of the curtain of secrecy. Makes interesting reading.

Dengue is a mosquito-borne disease caused by four serotypes of dengue virus (DENV1–DENV4) and is currently the most common arbovirus (arthropod-transmitted) disease worldwide. Primary infection with any of the four DV serotypes typically results in dengue fever (DF), a relatively mild influenza-like illness which subsequently provides lifelong immunity to the infecting strain. However, the bad news is that secondary infection with different DV serotype is associated with an increased risk of developing more serious conditions such as dengue haemorrhagic fever (DHF) and the life-threatening dengue shock syndrome (DSS).

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The first well documented outbreaks of dengue occurred in the eighteenth century, although the disease may have been around in China eight hundred years earlier. Dengue virus was first isolated by Japanese and American scientists during World War II. Dengue is now a major public health problem, with approximately 50 million people infected each year (of whom around 20,000 die) and nearly half the world’s population, about 3.5 billion people, at risk of infection. Unfortunately, no dengue virus-specific therapies or vaccines are currently available. The incidence of dengue infection has increased dramatically in the past 50 years. This is due in part to population growth and urbanization in tropical and subtropical countries. Originally found in the jungles and rural areas of Southeast Asia, dengue virus is now maintained primarily in an urban cycle involving human hosts and Aedes aegypti and A. albopictus mosquitoes. Urban areas frequently contain many breeding sites for the mosquitoes that transmit the virus, such as rain-filled old tyres. Successful mosquito control has also been problematic. Dengue viruses have evolved rapidly as they have spread worldwide, and genotypes associated with increased virulence have expanded from South and Southeast Asia into the Pacific and the Americas.

The pathogenesis of dengue haemorrhagic fever and dengue shock syndrome remain unclear. The requirement for a second infection with a different serotype of the virus suggested that antibody-dependent enhancement is involved in these more serious conditions. After an initial period of protection, antibodies from the primary infection can cross-react with other dengue virus serotypes but have waned to non-neutralizing levels. These non-neutralizing antibodies could then mediate an increased uptake of virus into monocyte/macrophage cells via Fc receptors, leading to increased virus replication and immune activation including massive cytokine release (known as a “cytokine storm”). An alternative theory involves reactivation of cross-reactive memory T cells specific for the previous rather than the current virus strain, resulting in delayed virus clearance and/or increased cytokine secretion along with increased apoptosis of both infected and uninfected bystander cells (known as “original antigenic sin”).

With only around 65% homology based on amino acid sequence, the four dengue viruses could have been classified as separate virus groups but instead are treated as four serotypes belonging to a single group. It appears that there may be differences between the viruses, with DENV2 most commonly been associated with DHF/DSS and DENV4 the least likely to cause the more serious infections, but all serotypes can cause all of the conditions.

Because of the nature of dengue virus pathogenesis, a tetravalent vaccine effective against all four dengue virus serotypes is urgently needed. Vaccines which induce weak immune responses below protective levels over time are not acceptable because of the severe consequences of secondary DENV infections. Efforts to develop a dengue vaccine have encompassed live attenuated virus vaccines, inactivated virus vaccines, subunit vaccines and DNA vaccines. Vaccines of each type are currently or have been subjected to clinical trials, but none has yet been approved for use. Travelers to affected regions should take precautions against being bitten by mosquitos, use insect repellent day and night and check that hotels provide mosquito nets. Just another joy of those long-haul holidays.

CDC: Dengue Fever
Global Spread and Persistence of Dengue. Ann Rev Microbiol Apr 22 2008
Prospects for a dengue virus vaccine. Nature Reviews Microbiology 2007 5: 518-528

Related:

• Pathogenic Flaviviruses
• Dengue virus infection activates the unfolded protein response
• Changing patterns of chikungunya virus
• Yellow Fever – Out of Africa

Haemorrhagic disease, encephalitis, biphasic fever, flaccid paralysis, and jaundice are typical manifestations of diseases in human beings after infections by mosquito-borne or tick-borne flaviviruses such as yellow fever, dengue, West Nile, St Louis encephalitis, Japanese encephalitis, tick-borne encephalitis, Kyasanur Forest disease, and Omsk haemorrhagic fever. Although the characteristics of these viruses are well defined, they are still unpredictable with increases in disease severity, unusual clinical manifestations, unexpected methods of transmission, long-term persistence, and the discovery of new species. This paper compares the epidemiological and clinical features of the medically important flaviviruses, consider the effect of human activity on their evolution and dispersal, and draw attention to new findings and some of the unanswered questions, unresolved issues, and controversies that remain.

Pathogenic flaviviruses. Lancet. 2008 371(9611): 500-509

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• Inhibition of apoptosis prevents West Nile virus cell damage
• Yellow Fever – Out of Africa