Friday, October 20, 2017

PLoS Comp. Bio.: Spring & Early Summer Most Likely Time For A Pandemic
Credit Spencer J. Fox


We've a new study, just published in PLoS Computational Biology, that looks at the history of 6 pandemics in the Northern Hemisphere since 1889, and finds they all first emerged in spring and early summer. Using a computer model, the authors found evidence of a narrow window of opportunity for pandemic emergence.
The authors then proposed two possible factors behind this trend, one of which long time readers of this blog will recall was a frequent topic of conversation after the last pandemic.
First some excerpts from a press release from the University of Texas At Austin, and a link and some excerpts from the study, then I'll return with a jaunt down memory lane. 

Cracking the Code: Why Flu Pandemics Come At the End of Flu Season

Oct. 19, 2017
You might expect that the risk of a new flu pandemic — or worldwide disease outbreak — is greatest at the peak of the flu season in winter, when viruses are most abundant and most likely to spread. Instead, all six flu pandemics that have occurred since 1889 emerged in spring and summer months. And that got some University of Texas at Austin scientists wondering, why is that?

Based on their computational model that mimics viral spread during flu season, graduate student Spencer Fox and his colleagues found strong evidence that the late timing of flu pandemics is caused by two opposing factors: Flu spreads best under winter environmental and social conditions. However, people who are infected by one flu virus can develop temporary immune protection against other flu viruses, slowing potential pandemics. Together, this leaves a narrow window toward the end of the flu season for new pandemics to emerge.

The researchers’ model assumes that people infected with seasonal flu gain long-term immunity to seasonal flu and short-term immunity to emerging pandemic viruses. The model incorporates data on flu transmission from the 2008-2009 flu season and correctly predicted the timing of the 2009 H1N1 pandemic.
(Continue . . . )

Seasonality in risk of pandemic influenza emergence

Spencer J. Fox , Joel C. Miller, Lauren Ancel Meyers

Published: October 19, 2017


Influenza pandemics can emerge unexpectedly and wreak global devastation. However, each of the six pandemics since 1889 emerged in the Northern Hemisphere just after the flu season, suggesting that pandemic timing may be predictable.
Using a stochastic model fit to seasonal flu surveillance data from the United States, we find that seasonal flu leaves a transient wake of heterosubtypic immunity that impedes the emergence of novel flu viruses. This refractory period provides a simple explanation for not only the spring-summer timing of historical pandemics, but also early increases in pandemic severity and multiple waves of transmission.
Thus, pandemic risk may be seasonal and predictable, with the accuracy of pre-pandemic and real-time risk assessments hinging on reliable seasonal influenza surveillance and precise estimates of the breadth and duration of heterosubtypic immunity.
         (Continue . .  ) 

Eight years ago, months after the 2009 H1N1 pandemic had emerged - but a couple of months before the monovalent H1N1 vaccine would be available - news of an unpublished Canadian study began to surface that suggested that those who had received a seasonal flu shot the previous year were more likely to contract the new pandemic virus than those who hadn’t.
Helen Branswell, science and medical reporter for the Canadian Press, was among the first to report on it (see Branswell On The Canadian Flu Shot Controversy).

The CDC and the World Health Organization both looked at their data, and issued statements that they could find no correlation between the seasonal vaccination and increased susceptibility to the pandemic flu.

With concerns rising, a number of Canadian Provinces halted or announced delays in rolling out the seasonal flu shot, even though the study had yet to be published (see Ontario Adjusts Vaccination Plan).
The debate raged on, with conflicting data (see here, here, and here), long after the 2009 pandemic ended.
In November of 2010, an article appeared in the Eurosurveillance Journal (see Eurosurveillance: The Temporary Immunity Hypothesis) that suggested that contracting seasonal flu (as opposed to being vaccinated against it) temporarily ramped up the body’s immune system against other viruses – and that this protective effect could last months.
Eurosurveillance, Volume 15, Issue 47, 25 November 2010

Seasonal influenza vaccination and the risk of infection with pandemic influenza: a possible illustration of non-specific temporary immunity following infection

H Kelly , S Barry, K Laurie, G Mercer

Unlike the Canadian researchers, these scientists could find no increased susceptibility to the pandemic H1N1 virus among Australians who had been vaccinated the previous year against seasonal flu. The difference between the two findings, they posited, came from three separate factors:

  • A theory regarding temporary immunity following any influenza infection
  • The timing of the arrival of the pandemic virus in Canada
  • And the protective effects of seasonal flu vaccination against seasonal - but not pandemic - flu.
While unproven, this hypothesis fits in nicely with the findings of today's study. 
Dr. Ian Mackay discussed a similar hypothesis in his blog back in 2014, in Influenza in Queensland, Australia: 1-Jan (Week 1) to 8-June (Week 23), where he suggested that the immune response to the early spread of one respiratory virus might dampen the spread of a second virus - perhaps for months - what he dubbed a `shields up' effect. 
While there could be other factors we don't know about that might override this proposed narrow window of opportunity for pandemics - based on the historical record and the growing evidence for the temporary immunity hypothesis - late spring and early summer do seem the most likely time for pandemic emergence.

WHO & Ugandan MOH Statements On Marburg Virus

Credit CDC


Overnight the World Health Organization emailed out a statement on yesterday's reported Marburg virus outbreak in Uganda (see Uganda's Virus Research Institute Confirms 2 Marburg Virus Deaths) and we have an initial statement from the Ugandan MOH as well.
While there are conflicting reports about how many cases are confirmed (WHO states: `One suspected and one probable case'), in the following statement we learn that hundreds may have been exposed at a traditional burial ceremony in Kween District.
First this, from WHO.
WHO supports containment of rare virus on Uganda-Kenya border

News release

20 October 2017 | GENEVA - WHO is working to contain an outbreak of Marburg virus disease (MVD) that has appeared in eastern Uganda on the border with Kenya.

At least one person is confirmed to have died of MVD and several hundred people may have been exposed to the virus at health facilities and at traditional burial ceremonies in Kween District, a mountainous area 300 kilometres northeast of Kampala.

The first case was detected by the Ministry of Health on 17 October, a 50-year-old woman who died at a health centre of fever, bleeding, vomiting and diarrhoea on 11 October. Laboratory testing at the Uganda Virus Research Institute (UVRI) confirmed the cause of death as MVD.

The woman’s brother had also died of similar symptoms three weeks earlier and was buried at a traditional funeral. He worked as a game hunter and lived near a cave inhabited by Rousettus bats, which are natural hosts of the Marburg virus.

One suspected and one probable case are being investigated and provided with medical care. An active search for people who may have been exposed to or infected by the virus is underway.

The Ministry of Health has sent a rapid response team to the area supported by staff from the World Health Organization, the Centers for Disease Control and Prevention (CDC) and the African Field Epidemiology Network (AFNET).

WHO is providing medical supplies, guidance on safe and dignified burials, and has released USD 500 000 from its Contingency Fund for Emergencies to finance immediate response activities.

“We are working with health authorities to rapidly implement response measures,” said Ibrahima-Soce Fall, WHO Regional Emergency Director for the Africa region. “Uganda has previously managed Ebola and Marburg outbreaks but international support is urgently required to scale up the response as the overall risk of national and regional spread of this epidemic-prone disease is high.”

Marburg virus disease is a rare disease with a high mortality rate for which there is no specific treatment.
        (Continue . . . )

And this detailed statement from Uganda's Ministry of Health.

Hon. Dr. Jane Ruth Aceng
Minister of Health
October 19, 2017


The Ministry of Health would like to inform the general public that there is a confirmed case of Marburg Virus Disease (MVD) in the country. This followed laboratory tests conducted by the Uganda Virus Research Institute (UVRI) which confirmed that one person had died of Marburg Virus Disease, a type of Viral Hemorrhagic Fevers (VHF) on 17th October 2017.

As at 19th October, 2017, only one case had been confirmed. The confirmed case was a 50-year-old female from Chemuron village, Moyok Parish, Moyok sub county, Kween District in Eastern Uganda. She presented with signs and symptoms suggestive of a Viral Hemorrhagic Fever (VHF) and unfortunately passed on during the night of October 11, 2017 at Kapchorwa Hospital, having been referred from Kaproron Health Center IV in Kween district.

Preliminary field investigations indicated that prior to her death; the deceased had nursed her 42-year-old brother, who had died on September 25, 2017 with similar signs and symptoms. She had also closely participated in the cultural preparation of the body for burial. The deceased’s brother was reported to be a hunter who carried out his activities where there are caves with heavy presence of bats. However, no samples were taken off his body prior to his death.

Marburg Virus Disease (MVD) is caused by the Marburg virus, a rare but severe type of Viral Hemorrhagic Fever which affects both humans and non-human primates like monkeys, baboons. The reservoir host of Marburg virus is the African fruit bat. Fruit bats infected with Marburg virus do not show obvious signs of illness. Primates (including humans) are vulnerable to contracting the Marburg virus, which is known to have a very high mortality.

In Marburg outbreaks, the first person normally gets infected through contact with infected bats or animals (normally monkeys/baboons). Once the first person (Index case) gets infected with the Marburg Virus, human to human transmission of Marburg Virus Disease (MVD) then occurs through contact with the body fluids (blood, vomitus, Urine, feces, etc) of already infected persons. Close contacts to already infected persons (like close family members of already infected persons) and health workers are particularly at increased risk of getting infected with the Marburg virus.

A person suffering from Marburg presents with sudden onset of high-grade fever accompanied by any of the following symptoms:

1. Headache
2. Vomiting blood
3. Joint and muscle pains
4. Unexplained bleeding through the body openings including the eyes, nose, gums, ears, anus and the skin.

There is no specific treatment or vaccine available for Marburg for now, but patients are given supportive treatment which supports the natural recovery process of the body and this improves tremendously the patient’s survival chances. However, treatment outcomes are better for those who seek care early.

To mitigate the current threat of Marburg Virus Disease, the Ministry of Health is undertaking the following measures to control the spread of the disease:

  • Ministry of Health has deployed a Rapid Response Team comprising of highly experienced Epidemiologists, Risk Communication experts, Case Management,
  • Infection Control and Prevention experts, ecological environmental experts, Laboratory specialists, among others to Kween and Kapchorwa districts. The team will support District Rapid Response Teams to investigate and assess the magnitude of the threat and to institute appropriate control measures to avert the Marburg Virus Disease threat.
  • An isolation ward at the Kapchorwa District Hospital and Kaproron Health Center IV in Kween District have been established to handle cases.
  • Preparations are underway to train all health workers, particularly from Kapchorwa Hospital, and Kaproron Health Centre IV on VHF Infection Prevention and Control. Infection Prevention and Control measures have been heightened in all health facilities in Kapchorwa and Kween districts.
  • Personal Protective Equipment (PPE’s) and other supplies have been mobilized to support response in the affected facilities.
  • The National Medical Stores is delivering emergency supplies to the affected health facilities.
  • Increasing awareness in affected communities and among health-care providers on the clinical symptoms of patients with Marburg Virus Disease.
Marburg Virus Disease has the potential to spread over wide areas affecting many people especially health workers and family members nursing Marburg Viral Disease patients.
The Ministry of Health therefore appeals to the general public to remain alert and observe the following precautions to control the spread of the Marburg virus:
  • Report any suspected patient immediately to a nearby health facility.
  • Avoid direct contact with body fluids of a person presenting with bleeding tendencies or symptoms suggestive of Marburg virus disease.
  • Health workers are further reminded to wear gloves and appropriate personal protective equipment when taking care of ill patients or suspected cases.
  • Regular hand washing is required after visiting patients in hospital, as well as after taking care of patients at home.
  • Avoid contact with persons who have died from the disease.
  •  Allow health workers perform dignified burials among victims who might have succumbed to the disease, so as to minimise its spread to others.
The Ministry of Health calls upon the general public to remain calm but be on alert amidst this epidemic. You can report all suspected cases via the Ministry of Health hotline on 0800100066.
For God and My Country
Hon. Dr. Jane Ruth Aceng
Minister of Health

Although most Marburg outbreaks over the past decade have been limited in size, after the horrific and unprecedented outbreak of Ebola in West Africa in 2014-15 - where 30,000+ people were infected and at least 11,000 people died - no one is taking this outbreak lightly.

Thursday, October 19, 2017

Madagascar MOH Update: 911 Cases Of Plague Reported (95 Deaths)


Madagascar's MOH has updated their plague statistics page adding 33 additional cases and 15 deaths since their last update 24 hours ago. Although the case count appears to be rising more slowly over the past few days, this is the biggest one-day jump in deaths (n=15) we've seen.
That said, the mortality rate - given the high percentage of pneumonic plague cases - has (so far) been relatively low.
This update from the BNGRC website.

Currently, 39 districts in 17 regions of Madagascar are affected by the epidemic of plague.
On this day, 911 cases were reported, including: 612 pulmonary forms, 175 forms bubonic and 124 unspecified.
The general assessment shows: 554 people who are already cured and taken out of the hospital, 262 people in treatment and 95 deaths.
The table below shows the number of cases cumulated by Region, since the beginning of the plague (status as of 18 October 2017)

Cell Host & Microbe: HPAI H7N9 Lethality & Transmission In Ferrets

Credit CDC MMWR Sept 2017


Since if first emerged in China in early 2013, LPAI (low path) H7N9 has been viewed as having enhanced pandemic potential - at least compared to other avian flu viruses.  While H7N9 appeared on the decline in its 3rd and 4th epidemic waves, last winter the number of cases in Mainland China literally exploded (see chart above), nearly equaling the total of the first four epidemic waves combined. 
The CDC's Influenza Risk Assessment Tool (IRAT) ranks the newly emerged Yangtze River Delta lineage along with the original Pearl River Delta Lineage (see Updating the CDC's IRAT (Influenza Risk Assessment Tool) Rankings) at the top of their list of viruses with the greatest pandemic potential.
But along with these LPAI viruses, a new HPAI (highly pathogenic) H7N9 virus emerged in Gaungdong province last winter, and quickly began to spread to other provinces. Although case reports are limited, there has been some early evidence suggesting this HPAI version might pose an even greater threat to human health (see Eurosurveillance: Epidemiology of Human HPAI H7N9 Infection - Guangdong Province).

So concerned have Chinese officials been over this HPAI version, this summer - for the first time -  China's MOA Ordered An HPAI H7N9 Vaccine Deployed Nationwide This Fall. It isn't known how effective this new vaccine will be, how well it can be deployed this winter, or what the fallout from using this vaccine might be (see New Scientist: The Downsides To Using HPAI Poultry Vaccines).
While avian influenza viruses have been a concern for nearly two decades, their public health impact has been limited by their inability to spread efficiently or in a sustained manner from human-to-human.  
Infections are generally (but not always) acquired from exposure to infected birds (or their environment) and are only rarely passed on. Avian flu viruses remain better adapted to avian hosts, rather than mammals. 
That said, we've seen increased signs of mammalian adaptation over the years (see Eurosurveillance: Genetic Tuning Of Avian H7N9 During Interspecies Transmission and Nature Comms.: NS Mutation Enhances H7N9's Ability To Infect Humans).
Although we've seen some preliminary analyses of this new HPAI H7N9 virus, today we get our most detailed look at how well it infects, and can be spread by, mammalian hosts.  And the headline is: HPAI H7N9 appears to be better adapted to mammalian hosts - and potentially a bigger pandemic threat - than its LPAI precursors.

Not only is this new HPAI H7N9 virus lethal in ferrets, it transmits well between them via respiratory droplets, and has shown an elevated level of resistance to oseltamivir (aka Tamiflu).
While not unexpected, these are the sorts of evolutionary changes in an HPAI virus that no one wants to see.
The study, conducted by an international team of researchers led by Yoshihiro Kawaoka, came off embargo today at noon. They tested a wild type HPAI H7N9 virus - along with two nearly identical lab created variants - one sensitive to oseltamivir and one with a mutation to make it resistant to the antiviral.
While the resistant strain wasn't quite as robust (or pathogenic) as the others, they all infected, replicated in, and caused varying degrees of illness in mice, ferrets and macaques.
First, some excepts from the press release provided by the University of Wisconsin-Madison, followed by a link to the 21 page, highly detailed and (fair warning) often technical study.

There's a lot here to absorb, and I've only included some excerpts, so you'll want to download and read both in their entirety. 

H7N9 influenza is both lethal and transmissible in animal model for flu
University of Wisconsin-Madison

MADISON, Wis. -- In 2013, an influenza virus that had never before been detected began circulating among poultry in China. It caused several waves of human infection and in late 2016, the number of people to become sick from the H7N9 virus suddenly started to rise. As of late July 2017, nearly 1,600 people had tested positive for avian H7N9. Nearly 40 percent of those infected had died.

In early 2017, Yoshihiro Kawaoka, professor of pathobiological sciences at the University of Wisconsin-Madison School of Veterinary Medicine, received a sample of H7N9 virus isolated from a patient in China who had died of the flu. He and his research team subsequently began work to characterize and understand it. The first of those results are published today (Oct. 19, 2017) in Cell Host & Microbe.

For the first time, Kawaoka says, his team has identified an influenza virus strain that is both transmissible between ferrets (the best animal model proxy for human influenza infections) and lethal, both in the animal originally infected and in otherwise healthy ferrets in close contact with these infected animals.

"This is the first case of a highly pathogenic avian virus that transmits between ferrets and kills them," Kawaoka says. "That's not good for public health."


H7N9 virus is likely to continue to mutate as it infects humans, resulting in adaptations that enhance the viruses' pathogenicity or ability to pass from person to person, Kawaoka adds. In other words, nature is already performing its own gain-of-function experiments, with potentially serious consequences.

It has, however, become a bit easier recently to detect when poultry are infected with H7N9, thereby allowing people to limit their exposure. That's because the virus has begun to kill birds in China, too. But unlike in the U.S., where farmers cull their flocks to limit the spread of infectious disease, China relies on vaccines. This worries Kawaoka, given how well the virus has been shown to grow.

For now, he says: "We should improve our surveillance."
(Continue . . . )

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets

Masaki Imai8,'Correspondence information about the author Masaki ImaiEmail the author Masaki Imai, Tokiko Watanabe8, Maki Kiso8, Noriko Nakajima8, Seiya Yamayoshi8, Kiyoko Iwatsuki-Horimoto8, Masato Hatta8, Shinya Yamada, Mutsumi Ito, Yuko Sakai-Tagawa, Masayuki Shirakura, Emi Takashita, Seiichiro Fujisaki, Ryan McBride, Andrew J. Thompson, Kenta Takahashi, Tadashi Maemura, Hiromichi Mitake, Shiho Chiba, Gongxun Zhong, Shufang Fan, Kohei Oishi, Atsuhiro Yasuhara, Kosuke Takada, Tomomi Nakao, Satoshi Fukuyama, Makoto Yamashita, Tiago J.S. Lopes, Gabriele Neumann, Takato Odagiri, Shinji Watanabe, Yuelong Shu, James C. Paulson, Hideki Hasegawa, Yoshihiro Kawaoka9,'

Correspondence (M.I.), (Y.K.)

In Brief

Highly pathogenic avian influenza (HPAI) H7N9 viruses have emerged and raised concerns of a pandemic. Imai et al.characterized an HPAI H7N9 virus isolated from a human. This virus transmitted among ferrets without prior adaptation and caused lethal infection in animals, demonstrating its pandemic potential and the need for surveillance.


    • Highly pathogenic avian influenza (HPAI) H7N9 viruses replicate efficiently in mammals
    • HPAI H7N9 viruses are more pathogenic than low pathogenic H7N9 viruses in mammals
    • HPAI H7N9 viruses transmit via respiratory droplets among ferrets
    • HPAI H7N9 viruses show low sensitivity to neuraminidase inhibitors in mice

(Continue . . . .)

While concerning, none of this guarantees that H7N9 will spark a human pandemic. There may yet be some species specific barrier - or some other obstacle - that could prevent that from happening.
What this study does suggest is that the recently emerged HPAI H7N9 virus appears further along the evolutionary path that could eventually take it in that direction than the other viruses we've been following.
I expect this study will spark a good deal of discussion in the coming days, along with renewed calls for pandemic preparedness. Because - while the cause of the next pandemic may still be in doubt - another pandemic is considered more or less inevitable.

Uganda's Virus Research Institute Confirms 2 Marburg Virus Deaths


While not as well known as the Ebola viruses, Marburg was the first of the filovirus family of hemorrhagic diseases to be recognized. Normally only found in parts of eastern and central Africa, Marburg – surprisingly - was first detected in Germany in the late 1960s.
In 1967, several workers involved with Polio research at a laboratory in Marburg, Germany fell ill with an unknown illness. What began with fever, vomiting, and diarrhea progressed rapidly to internal bleeding, shock, and for 7 of the 31 victims, death.
An investigation identified the source of the virus: Green monkeys imported from Uganda for research, and in time, the virus was isolated.This  lead to the creation of a new virus family; the Filoviridae, of which Marburg and the five Ebola viruses are the principal members.

Over the past five decades Marburg outbreaks have has only appeared sporadically.  In South Africa in 1975 (3 cases), Kenya in 1980 (2 cases) and again in 1987 (1 case), and in a pair of laboratory accidents in the Soviet Union in 1988 and 1990.

Between 1998 and 2000 more than 150 cases were recorded in the Democratic Republic of the Congo, and a second marburgvirus (RAVV) was identified. In 2004-2005, the largest known outbreak occurred in Angola, where 90% of the 252 cases died (see the CDC’s MMWR report from 2005).

Over the past five years Uganda has reported two outbreaks; in October of 2012 (see Here) and again in October of 2014 (see Here).

Credit CDC

Like with Ebola viruses, bats are believed to be the reservoir host for Marburg, although it isn't known what other hosts might carry the virus.  Human infection is often attributed to the consumption of bush meat.

Yesterday Uganda's Virus Research Institute posted the following statement on their Facebook page.  

Uganda Virus Research Institute added 3 new photos.
Yesterday at 6:19am ·

UVRI confirms cases of the deadly Marburg virus in Kween District in Eastern Uganda.

Uganda Virus Research Institute has confirmed cases of the deadly Marburg virus in Kween District on the western slopes of Mt. Elgon in Eastern Uganda. Two people have died from the deadly hemorrhagic fever.

The Ministry of health is sending an emergency response team to the district.
The public is urged to be vigilant and report suspected cases.

Symptoms of the marburg virus include Nausea and vomiting, Diarrhea (may be bloody), Red eyes, Raised rash, Chest pain and cough, Sore throat, Stomach pain, Severe weight loss among others.

This morning a number of news agencies have published the story, although the details (whether one or two cases have died) differ.   Typical is this from the Ugandan.

Deadly Marburg virus kills two in Kween district, govt confirms

The Ministry of health has sent a team of epidemiologists to Kween district, following the confirmation of an outbreak of the deadly Marburg haemorrhagic fever, which has so far claimed the lives of two people.

The team led by the Director General of Health Services is in Kween district to sensitise residents about the disease, and prevent further spread.

Yesterday, the Ministry confirmed that two people who died early this week, had succumbed to the Marburg haemorrhagic fever.

The deceased were admitted at Kaproron Health Centre Four between September and October.

Marburg hemorrhagic fever is a highly contagious and severe illness that affects both humans and non-human primates

Despite all of these reports, Uganda's Ministry of Health website has yet to post anything on these cases.

Wednesday, October 18, 2017

Madagascar MOH: 878 Cases Of Plague Reported (80 Deaths)


Madagascar's MOH has updated their plague statistics page adding 73 cases and 6 deaths since their last updated tally on Monday.

The situation of the plague epidemic currently affects 39 Districts,in 17 regions of Madagascar.

For the time being, 878 cases of plague have been recorded for the whole country. The balance sheet reports 80 deaths.

As of today, 44 new cases (27 Antananarivo-Analamanga, 5 Toamasina- Atsinanana, 4 Vakinankaratra, 1 Bongolava, 4 High Matsiatra, 1 Alaotra Mangoro, 1 Amoron'i Mania and 1 Analanjirofo) and 4 deaths (3 Antananarivo-Analamanga and 1 Toamasina-Atsinanana) were observed.
(Source: Ministry of Public Health - 18 October 2017)
 The following figure shows the distribution of the plague situation (by Region) registered to date.