Simplified rabies vaccination

A simplified economical method of giving rabies vaccine is just as effective as the expensive standard vaccination method at stimulating anti-rabies antibodies. A clinical trial in healthy volunteers has found that a simpler and cheaper way of using rabies vaccines proved to be just as effective as the current most widely used method at stimulating antibodies against rabies. The trial is published in this week’s PLoS Neglected Tropical Diseases. Dr Mary Warrell (Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford) and colleagues, who conducted the trial with a vaccine in routine use, say that the simplified method has the advantages of requiring fewer clinic visits, being more practicable, and acceptable, and having a wider margin of safety, especially in inexperienced hands. It would therefore be suitable for use anywhere in the world where there are financial constraints, and especially where two or more patients are likely to be treated on the same day.

All human deaths from rabies result from failure to give adequate prophylaxis. After a rabid animal bite, immediate wound cleaning, rabies vaccine and injections of anti-rabies antibody (immunoglobulin) effectively prevent fatal infection. But anti-rabies immunoglobulin is very rarely available in developing countries, and so prevention relies on giving people bitten by rabid animals effective vaccine treatment. The vaccines that are currently approved by the World Health Organization, which are usually injected into the muscle, are prohibitively expensive, and so are unaffordable in developing countries. In Africa, for example, the average cost of an intramuscular course of vaccine is $US 39.6, equivalent to 50 days wages.

Two more economical regimes, involving injecting small amounts of vaccine into the skin (intradermally) at 2 or 8 sites on the first day of the course with subsequent booster doses, are available in a few places. With the 8-site method, a large dose of vaccine is given on the first day only, whereas with the 2-site method the same dose is divided between the first and third days, entailing an extra visit to the clinic. However, practical or perceived difficulties have restricted widespread uptake of these economical methods. Dr Warrell and colleagues set out to test a new, similar simplified regime, involving injections at 4 sites on the first day. They vaccinated healthy volunteers to compare the antibody levels induced by the 4-site intradermal regimen with those induced by the current 2-site and 8-site intradermal regimes and the “gold standard” intramuscular regimen favored internationally. All of the economical intradermal methods worked just as well as the intramuscular method at stimulating anti-rabies antibodies. The authors conclude that the results provide sufficient evidence that the simplified 4-site regimen now meets all the criteria necessary for its recommendation for use wherever the cost of vaccine is prohibitive.

A Simplified 4-Site Economical Intradermal Post-Exposure Rabies Vaccine Regimen: A Randomised Controlled Comparison with Standard Methods. 2008 PLoS Negl Trop Dis 2(4): e224

Measles vaccination and SSPE

When measles vaccines were widely introduced in the 1970s, there were concerns that they might cause subacute sclerosing panencephalitis (SSPE), a very rare, late-onset, neurological complication of natural measles infection. Therefore, SSPE registries and routine measles immunization were established in many countries concurrently. We conducted a comprehensive review of the impact of measles immunization on the epidemiology of SSPE and examined epidemiological evidence on whether there was any vaccine-associated risk. Published epidemiological data on SSPE, national SSPE incidence, measles incidence and vaccine coverage, reports of SSPE in pregnancy or shortly post partum were reviewed. Potential adverse relationships between measles vaccines and SSPE were examined using available data. Epidemiological data showed that successful measles immunization programmes protect against SSPE and, consistent with virological data, that measles vaccine virus does not cause SSPE. Measles vaccine does not: accelerate the course of SSPE; trigger SSPE or cause SSPE in those with an established benign persistent wild measles infection. Evidence points to wild virus causing SSPE in cases which have been immunized and have had no known natural measles infection. Perinatal measles infection may result in SSPE with a short onset latency and fulminant course. Such cases are very rare. SSPE during pregnancy appears to be fulminant. Infants born to mothers with SSPE have not been subsequently diagnosed with SSPE themselves. Successful measles vaccination programmes directly and indirectly protect the population against SSPE and have the potential to eliminate SSPE through the elimination of measles. Epidemiological and virological data suggest that measles vaccine does not cause SSPE.

Review of the effect of measles vaccination on the epidemiology of SSPE
Int J Epidemiol. 2007 36: 1334-1348

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Good Germs, Bad Germs: Health and Survival in a Bacterial World

Both friendly and destructive bacteria live in our mouths, eyes, skin and elsewhere. Over millions of years, the body has come to an accommodation with those creatures, generally striking a balance ensuring survival. This balance has been severely offset in recent years, due to a “cleanliness” obsession that arose when it became clear that some germs were responsible for diseases. This idea was effectively demonstrated by UK researcher David Strachan, whose research led to what is now called the “hygiene hypothesis” - respiratory illnesses result from lack of cross-microbe activity to build immunities. In short, rich, small families were more prone to allergies than large, poorer ones. As Sachs points out, humans in our society overreacted to the new knowledge about disease-causing germs and sought to eliminate them all. The imbalance has led to many tragic situations, and initiated a guarantee that more, perhaps worse, situations are in the offing. What are we to do about it?

Jessica Sachs guides us through the findings of scores of scientists’ work that has revised the approach we were taught about “germs” in our childhood. Eating mud, something many of us were at least verbally chastised for, turns out to be a good thing, even a necessity. From birth, the introduction of certain microbes initiate processes the body needs to keep going. For most people today, it’s well known that microbes in our tummies are part of the process of digestion. Escherichia coli is known to be a true friend - in controlled numbers and certain strains. What’s less known is how many other bacteria the body relies on to get certain jobs done. One of those jobs is keeping the immune system properly tuned. A lazy immune system is unresponsive or unable to react to invasion. An overly ambitious one can turn on its own body and destroy it.

Publisher Hill & Wang, Oct 2007, ISBN-10: 0809050633

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How Noroviruses cause repeated outbreaks of gastroenteritis

Noroviruses are the leading cause of viral gastroenteritis (stomach flu), the symptoms of which include nausea, vomiting, and diarrhoea. There is no treatment for infection with these highly contagious viruses. While most people recover within a few days, the very young and old may experience severe disease. Like influenza, large outbreaks (epidemics) of Norovirus infection occur periodically (often in closed communities such as cruise ships), and most people have several Norovirus infections during their lifetime. Currently, many people are being infected each week in England with a new GII.4 variant. There are several reasons for this pattern of infection and reinfection. First, the immune response induced by a Norovirus infection is short-lived in some people, but not all. Second, there are many different noroviruses. Based on their genomes, noroviruses belong to five genogroups, which are further subdivided into genotypes. An immune response to one Norovirus provides little protection against noroviruses of other genogroups or genotypes. Third, like influenza viruses, noroviruses frequently acquire small changes in their genome. This process is called antigenic drift. Norovirus epidemics occur when virus variants emerge to which the human population has no immunity.

It is unknown exactly how noroviruses change over time or how they persist in human populations. In addition, little is known about susceptibility to Norovirus infections except that secretor-positive individuals people who express histoblood group antigens (HBGA) on the cells that line their mouths and guts are more susceptible than secretor-negative people, who express these antigens only on red blood cells. Information of this sort is needed to devise effective intervention strategies, therapies, and vaccines to reduce the illness and economic costs associated with norovirus outbreaks. In this study, the researchers investigate the molecular mechanisms governing the emergence and persistence of epidemic norovirus strains in human populations by analyzing how GII.4 Norovirus strains (the genotype usually associated with epidemics) have changed over time.

These findings suggest that the part of the Norovirus capsid protein that binds to sugars on host cells is under heavy immune selection and evolves over time by antigenic drift. They show that, like influenza viruses, GII.4 viruses evolve through serial changes in the capsid sequence that occur sporadically after periods of stability, probably to evade the build up of immunity within the human population. Variation in this region of the viral genome is possible because human populations express a great variety of HBGA molecules so there is always likely to be a subpopulation of people that is susceptible to the altered virus. Overall, these findings suggest that it should be possible to develop vaccines to protect against Norovirus infections but, just as with influenza virus, surveillance systems will have to monitor how the virus is changing and vaccines will need to be reformulated frequently to provide effective protection against Norovirus outbreaks.

Mechanisms of GII.4 Norovirus Persistence in Human Populations. PLoS Medicine 5, 2, e31
Our data suggest that the surface-exposed carbohydrate ligand binding domain in the Norovirus capsid is under heavy immune selection and likely evolves by antigenic drift in the face of human herd immunity. Variation in the capsid carbohydrate-binding domain is tolerated because of the large repertoire of similar, yet distinct HBGA carbohydrate receptors available on mucosal surfaces that could interface with the remodeled architecture of the capsid ligand-binding pocket. The continuing evolution of new replacement strains suggests that, as with influenza viruses, vaccines could be targeted that protect against Norovirus infections, and that continued epidemiologic surveillance and reformulations of Norovirus vaccines will be essential in the control of future outbreaks.

Metagenomic Analysis of Human Diarrhoea

Diarrhoea is one of the leading infectious causes of death worldwide with an estimated 1.8 million deaths annually, primarily in young children in developing countries. There are many known causes of diarrhoea; however, the causes of up to 40% of the cases are still unknown. One possibility is that viruses that we currently do not know about are responsible for these cases. The advent of metagenomic sequencing has enabled systematic and unbiased characterization of microbial populations; thus, metagenomic approaches have the potential to define the spectrum of viruses, including novel viruses, present in stool during episodes of acute diarrhoea. The detection of novel or unexpected viruses would then enable investigations to assess whether these agents play a causal role in human diarrhoea.

This paper uses an experimental strategy termed “micro-mass sequencing” to systematically identify viruses present in stool from a number of patients suffering from diarrhoea. Using this methodology we detected known enteric viruses as well as multiple sequences from putatively novel viruses with only limited sequence similarity to viruses in GenBank. Sequences from a number of novel viruses were detected, some which differed quite significantly from any previously described virus. These new viruses may or may not be responsible for causing diarrhoea. Future studies will specifically address the potential of these viruses to cause human disease. One implication of this study is that there are likely to be many more unknown viruses that can be identified in this fashion. Furthermore, by studying these viruses, we will come to a more complete understanding of the role viruses play in diarrhoea. Ultimately, this may lead to the development of therapeutics and/or vaccines that decrease the disease burden of diarrhoea.

Metagenomic Analysis of Human diarrhoea: Viral Detection and Discovery
PLoS Pathog 2008 4(2): e1000011

HIV-1 gp120 induces immunosuppressive responses from dendritic cells

Dendritic cells (DCs) initiate immune responses to pathogens or vaccine antigens. The HIV-1 gp120 envelope glycoprotein is an antigen that is a focus of vaccine design strategies. gp120 can signal via several cell surface receptors. A recent paper studied how gp120 proteins interact with DCs in cell culture. Certain gp120s stimulate DCs from some, but not all, human donors to produce IL-10, a cytokine that is generally immunosuppressive. In addition, whether or not the DCs produce IL-10, their ability to mature properly when activated is impaired by gp120 - the gp120-treated DCs have a reduced ability to stimulate T cell growth when the two cell types are cultured together. These various effects of gp120 are caused by its binding to cell surface receptors of the mannose C-type lectin receptor family, including (but probably not exclusively) one called DC-SIGN. gp120 binds to these receptors via mannose residues that are present on some of the glycan structures that overlay much of its protein surface. Removing the mannoses by digesting gp120 with a suitable enzyme prevents IL-10 induction and impairment of DC maturation, as does the use of inhibitors of the binding of gp120 to DC-SIGN and similar receptors. Such immunosuppressive mechanisms might suppress immune responses to Env-containing vaccines, demannosylation may be a way to improve the immunogenicity of gp120 or gp140 proteins.

HIV-1 gp120 Mannoses Induce Immunosuppressive Responses from Dendritic Cells. PLoS Pathog 2007 3(11): e169

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HIV “can never be cured”

A controversial news commentary in the subscription-only journal Nature on 14th February (Happy Valentine’s Day) reports on

HIV’s status as an ‘incurable’ infection, although in many cases doctors are able to stave off the onset of full-blown AIDS by giving patients sustained courses of drugs.

This item was based on an article published in May 2007:

Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus.
J Infect Dis. 2007 195:1762-1764
The persistence of latently infected resting CD4+ T cells has been clearly demonstrated in human immunodeficiency virus (HIV)-infected individuals receiving effective antiviral therapy. However, estimates of the half-life of this viral reservoir have been quite divergent. We demonstrate clear evidence for decay of this HIV reservoir in patients who initiated antiviral therapy early in infection. The half-life of this latent viral reservoir was estimated to be 4.6 months. It is projected that it will take up to 7.7 years of continuous therapy to completely eliminate latently infected resting CD4+ T cells in infected individuals who initiate antiviral therapy early in HIV infection.

which was recently backed up by a second publication from the same research group:

Persistence of HIV in Gut-Associated Lymphoid Tissue despite Long-Term Antiretroviral Therapy.
J Infect Dis. 2008 Feb 8
Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4(+) T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4(+) T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4(+) T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around the GALT of HIV-infected individuals despite long-term viral suppression and suggest that the GALT may play a major role in the persistence of HIV in such individuals.

Many HIV patients can manage their infection with a cocktails of antiretroviral drugs which can reduce their “viral load” - the amount of virus circulating in the blood plasma - to undetectable levels. But this work shows that even in such “non-infectious” patients HIV is still lurking in gut tissues, and still infecting other immune cells in the blood. It might not ever be possible to completely eradicate the virus from the body, even though people are doing well, says Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases.

MMR: our children, our choice?

In 2002, the BBC’s Panorama series included an edition entitled MMR: Every Parent’s Choice which investigated the origins of the controversy over measles, mumps and rubella (MMR) vaccination in the UK. In particular, the programme focussed on the role of Dr Andrew Wakefield and his, now refuted, claims concerning the link between the use of “triple-jab” MMR vaccine and childhood autism and bowel disease. Although the public controversy surrounding this vaccination has now largely been settled, MMR uptake still remains below the level required to ensure population (or “herd”) immunity…

Read more

Measles in sub-Saharan Africa

Although vaccination has almost eliminated measles in parts of the world, the disease remains a major killer in some high birth rate countries of the Sahel. On the basis of measles dynamics for industrialized countries, high birth rate regions should experience regular annual epidemics. This article shows that measles epidemics in Niger are highly episodic, particularly in the capital Niamey. Models demonstrate that this variability arises from powerful seasonality in transmission - generating high amplitude epidemics - within the chaotic domain of deterministic dynamics. In practice, this leads to frequent stochastic fadeouts, interspersed with irregular, large epidemics. A metapopulation model illustrates how increased vaccine coverage, but still below the local elimination threshold, could lead to increasingly variable major outbreaks in highly seasonally forced contexts. Such erratic dynamics emphasize the importance both of control strategies that address build-up of susceptible individuals and efforts to mitigate the impact of large outbreaks when they occur.

The dynamics of measles in sub-Saharan Africa. 2008 Nature 451: 679-684

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T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection

The human genome contains a number of remnants or fossils of ancient viral infections referred to as human endogenous retroviruses (HERV). Like fossils, these HERV are usually considered to be dead or inert as under normal circumstances, HERVs are functionally defective or controlled by host factors. However, recent work has demonstrated that T cells in the human immune system respond to HERV when a person is infected with the human immunodeficiency virus (HIV). In HIV-1-infected individuals, intracellular defense mechanisms are compromised. The T cells responding to HERV share characteristics with T cells that effectively control cytomegalovirus, a common chronic viral infection. T cells responding to HERV can also kill target cells carrying HERV protein. For some HIV-positive people, the strength of their response against HERV is related to having a lower HIV viral load. This study has important implications for new directions in HIV vaccine research. One of the key obstacles to creating an effective HIV vaccine is overcoming the ability of some of the virus variants produced when HIV evades the immune responses that the body mounts to control infections.

The authors hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. They show that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, they examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. There was an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design. If T cells that recognize HERV can stably target HIV-infected cells, they could be an important factor in controlling HIV infection.

T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection. 2007 PLoS Pathog 3(11): e165

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