- Cross-Neutralizing and Protective Human Antibody Specificities to Poxvirus Infections. [Journal Article]
- CellCell 2016 Oct 20; 167(3):684-694.e9
- Monkeypox (MPXV) and cowpox (CPXV) are emerging agents that cause severe human infections on an intermittent basis, and variola virus (VARV) has potential for use as an agent of bioterror. Vaccinia i...
Monkeypox (MPXV) and cowpox (CPXV) are emerging agents that cause severe human infections on an intermittent basis, and variola virus (VARV) has potential for use as an agent of bioterror. Vaccinia immune globulin (VIG) has been used therapeutically to treat severe orthopoxvirus infections but is in short supply. We generated a large panel of orthopoxvirus-specific human monoclonal antibodies (Abs) from immune subjects to investigate the molecular basis of broadly neutralizing antibody responses for diverse orthopoxviruses. Detailed analysis revealed the principal neutralizing antibody specificities that are cross-reactive for VACV, CPXV, MPXV, and VARV and that are determinants of protection in murine challenge models. Optimal protection following respiratory or systemic infection required a mixture of Abs that targeted several membrane proteins, including proteins on enveloped and mature virion forms of virus. This work reveals orthopoxvirus targets for human Abs that mediate cross-protective immunity and identifies new candidate Ab therapeutic mixtures to replace VIG.
- MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T-cells in healthy adults. [Journal Article]
- BloodBlood 2016 Oct 19
- Attenuated poxvirus Modified vaccinia Ankara (MVA) is a useful viral-based vaccine for clinical investigation, because of its excellent safety profile and property of inducing potent immune responses...
Attenuated poxvirus Modified vaccinia Ankara (MVA) is a useful viral-based vaccine for clinical investigation, because of its excellent safety profile and property of inducing potent immune responses against recombinant (r) antigens. We developed Triplex by constructing an rMVA encoding three immunodominant CMV antigens which stimulates a host anti-viral response: UL83 (pp65), UL123 (IE1-exon4), and UL122 (IE2-exon5). We completed the first clinical evaluation of the Triplex vaccine in 24 healthy adults, with or without immunity to CMV and vaccinia virus (previous DryVax smallpox vaccination). Three escalating dose levels (DL) were administered intramuscularly in 8 subjects/DL, with an identical booster injection 28 days later and one year follow-up. Vaccinations at all DL were safe with no dose limiting toxicities. No vaccine-related serious adverse events were documented. Local and systemic reactogenicity were transient and self-limiting. Robust, functional and durable Triplex driven expansions of CMV-specific T-cells were detected by measuring T-cell surface levels of 4-1BB (CD137), binding to CMV-specific HLA multimers, and IFN-γ production. Marked and durable CMV-specific T-cell responses were also detected in Triplex vaccinated CMV-seronegatives, and in DryVax vaccinated subjects. Long-lived memory effector phenotype, associated with viral control during CMV primary infection was predominantly found on the membrane of CMV-specific and functional T-cells, while off-target vaccine responses activating memory T-cells from the related herpesvirus EBV remained undetectable. Combined safety and immunogenicity results of MVA in allogeneic hematopoietic stem cell transplant recipients (HCT) and Triplex in healthy adults motivated the initiation of a placebo-controlled multicenter trial of Triplex in HCT patients. This study is registered as NCT01941056 @ www.clinicaltrials.gov.
- Estimating the Size of the U.S. Population at Risk of Severe Adverse Events from Replicating Smallpox Vaccine. [Journal Article]
- PHPublic Health Nurs 2016 Oct 13
- CONCLUSIONS: These figures are significant and larger than the only previously published study. Understanding this number allows for improved clinical utilization, equitable attention to the health needs of a vulnerable population, and strategic vaccine stockpiling.
- History of Smallpox and Its Spread in Human Populations. [Journal Article]
- MSMicrobiol Spectr 2016; 4(4)
- Smallpox is considered among the most devastating of human diseases. Its spread in populations, initiated for thousands of years following a probable transmission from an animal host, was concomitant...
Smallpox is considered among the most devastating of human diseases. Its spread in populations, initiated for thousands of years following a probable transmission from an animal host, was concomitant with movements of people across regions and continents, trade and wars. Literature permitted to retrace the occurrence of epidemics from ancient times to recent human history, smallpox having affected all levels of past society including famous monarchs. The disease was officially declared eradicated in 1979 following intensive vaccination campaigns.Paleomicrobiology dedicated to variola virus is restricted to few studies, most unsuccessful, involving ancient material. Only one recent approach allowed the identification of viral DNA fragments from lung tissue of a 300-year-old body excavated from permafrost in Eastern Siberia; phylogenetic analysis revealed that this ancient strain was distinct from those described during the 20th century.
- Cholera. [Journal Article]
- MSMicrobiol Spectr 2016; 4(4)
- Cholera is an acute disease of the gastrointestinal tract caused by Vibrio cholerae. Cholera was localized in Asia until 1817, when a first pandemic spread from India to several other regions of the ...
Cholera is an acute disease of the gastrointestinal tract caused by Vibrio cholerae. Cholera was localized in Asia until 1817, when a first pandemic spread from India to several other regions of the world. After this appearance, six additional major pandemics occurred during the 19th and 20th centuries, the latest of which originated in Indonesia in the 1960s and is still ongoing. In 1854, a cholera outbreak in Soho, London, was investigated by the English physician John Snow (1813 to 1858). He described the time course of the outbreak, managed to understand its routes of transmission, and suggested effective measures to stop its spread, giving rise to modern infectious disease epidemiology. The germ responsible for cholera was discovered twice: first by the Italian physician Filippo Pacini during an outbreak in Florence, Italy, in 1854, and then independently by Robert Koch in India in 1883, thus favoring the germ theory over the miasma theory of disease. Unlike many other infectious diseases, such as plague, smallpox, and poliomyelitis, cholera persists as a huge public health problem worldwide, even though there are effective methods for its prevention and treatment. The main reasons for its persistence are socioeconomic rather than purely biological; cholera flourishes where there are unsatisfactory hygienic conditions and where a breakdown of already fragile sanitation and health infrastructure occurs because of natural disasters or humanitarian crises.
- A translation of the Linnaean dissertation The Invisible World. [Journal Article]
- BJBr J Hist Sci 2016; 49(3):353-382
- This study presents the first translation from Latin to English of the Linnaean dissertation Mundus invisibilis or The Invisible World, submitted by Johannes Roos in 1769. The dissertation highlights...
This study presents the first translation from Latin to English of the Linnaean dissertation Mundus invisibilis or The Invisible World, submitted by Johannes Roos in 1769. The dissertation highlights Linnaeus's conviction that infectious diseases could be transmitted by living organisms, too small to be seen. Biographies of Linnaeus often fail to mention that Linnaeus was correct in ascribing the cause of diseases such as measles, smallpox and syphilis to living organisms. The dissertation itself reviews the work of many microscopists, especially on zoophytes and insects, marvelling at the many unexpected discoveries. It then discusses and quotes at length the observations of Münchhausen suggesting that spores from fungi causing plant diseases germinate to produce animalcules, an observation that Linnaeus claimed to have confirmed. The dissertation then draws parallels between these findings and the contagiousness of many human diseases, and urges further studies of this 'invisible world' since, as Roos avers, microscopic organisms may cause more destruction than occurs in all wars.
- DA Henderson, Smallpox Eradicator. [Journal Article]
- AJAm J Public Health 2016; 106(11):1895
- Donald Ainslie Henderson (1928-2016). [Journal Article]
- NatNature 2016 Oct 05; 538(7623):42
- Characterizing the reproduction number of epidemics with early subexponential growth dynamics. [Journal Article]
- JRJ R Soc Interface 2016; 13(123)
- Early estimates of the transmission potential of emerging and re-emerging infections are increasingly used to inform public health authorities on the level of risk posed by outbreaks. Existing method...
Early estimates of the transmission potential of emerging and re-emerging infections are increasingly used to inform public health authorities on the level of risk posed by outbreaks. Existing methods to estimate the reproduction number generally assume exponential growth in case incidence in the first few disease generations, before susceptible depletion sets in. In reality, outbreaks can display subexponential (i.e. polynomial) growth in the first few disease generations, owing to clustering in contact patterns, spatial effects, inhomogeneous mixing, reactive behaviour changes or other mechanisms. Here, we introduce the generalized growth model to characterize the early growth profile of outbreaks and estimate the effective reproduction number, with no need for explicit assumptions about the shape of epidemic growth. We demonstrate this phenomenological approach using analytical results and simulations from mechanistic models, and provide validation against a range of empirical disease datasets. Our results suggest that subexponential growth in the early phase of an epidemic is the rule rather the exception. Mechanistic simulations show that slight modifications to the classical susceptible-infectious-removed model result in subexponential growth, and in turn a rapid decline in the reproduction number within three to five disease generations. For empirical outbreaks, the generalized-growth model consistently outperforms the exponential model for a variety of directly and indirectly transmitted diseases datasets (pandemic influenza, measles, smallpox, bubonic plague, cholera, foot-and-mouth disease, HIV/AIDS and Ebola) with model estimates supporting subexponential growth dynamics. The rapid decline in effective reproduction number predicted by analytical results and observed in real and synthetic datasets within three to five disease generations contrasts with the expectation of invariant reproduction number in epidemics obeying exponential growth. The generalized-growth concept also provides us a compelling argument for the unexpected extinction of certain emerging disease outbreaks during the early ascending phase. Overall, our approach promotes a more reliable and data-driven characterization of the early epidemic phase, which is important for accurate estimation of the reproduction number and prediction of disease impact.
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- NSNurs Stand 1996 May 1; 10(32):6
- Happy Birth Day: School nurse Antonia Mead, and her nine-month old baby, laid a rose at Edward Jenner's statue in London's Kensington Gardens last week, to commemorate the 200th anniversary of Dr Jen...
Happy Birth Day: School nurse Antonia Mead, and her nine-month old baby, laid a rose at Edward Jenner's statue in London's Kensington Gardens last week, to commemorate the 200th anniversary of Dr Jenner's discovery of the smallpox vaccine.