Date: Mon 1 Jul 2019
Source: EurekAlert!, American Association for the Advancement of Science (AAAS) [edited]
<https://www.eurekalert.org/pub_releases/2019-07/fda-yfv070119.php>

The origin of the virus responsible for the ongoing yellow fever epidemic in Brazil, the worst for 40 years, has just been identified by scientists affiliated with 2 Brazilian institutions: Adolfo Lutz Institute (IAL) and the University of Sao Paulo (USP).

By means of a molecular study of yellow fever viruses found in dead monkeys and in mosquitoes, the group discovered that the strain behind the current epidemic originated in Para state in North Brazil in 1980.

The virus infected monkeys in Para and spread from there throughout the Amazon region until it reached Venezuela and Suriname. From 2000 on, always via infection of monkeys, the disease migrated to the Center-West and Southeast of Brazil, finally reaching Sao Paulo state in 2013. The 1st deaths of humans in Sao Paulo occurred in 2016.

Findings of the study, which was supported by Sao Paulo Research Foundation - FAPESP, are published in Scientific Reports [see reference below].

The investigation was led by Mariana Sequetin Cunha, a researcher in IAL's Vector-Borne Disease Group. Scientists at the University of Sao Paulo's Tropical Medicine Institute (IMT-USP), the Federal University of Para (UFPA) and the Federal University of Sao Paulo (UNIFESP) also took part. The project was also funded by Brazil's National Council for Scientific and Technological Development (CNPq).

Since mid-2016, when the ongoing yellow fever epidemic began, 2245 cases of the disease have been confirmed, with 764 deaths, according to the Health Ministry. The largest number of cases since 1980, when the government made notification mandatory, had previously been reported in 2000. In that year, 40 people died from yellow fever.

Another face of the problem is the infection of monkeys by the same mosquitoes that transmit the virus to humans. Since 2016, public health authorities responsible for epidemiological surveillance in the Center-West, Southeast, and South, where the epidemic is concentrated, have collected the carcasses of more than 10 000 monkeys found in forests and parks, mainly howler monkeys (_Alouatta_ spp.), marmosets (_Callithrix_ spp.) and capuchins (_Sapajus_ spp). Yellow fever virus was detected in 3403, according to the Health Ministry (Boletim Epidemiologico de Febre Amarela/Yellow Fever Epidemiological Bulletin).  "More than 90% of the dead monkeys are believed to be _Alouatta guariba_ [brown howler monkey]. The species is extremely susceptible to yellow fever," said Ester Sabino, Director of IMT-USP.  "Troops of more than 80 monkeys were entirely destroyed," Cunha said, referring to the deaths of howler monkeys from yellow fever in Horto Florestal, a nature reserve in the north of Sao Paulo city in late 2017.

Yellow fever is an acute disease caused by a virus transmitted to monkeys and humans through the bites of infected mosquitos. The symptoms include jaundice, a yellowish or greenish pigmentation of the skin and whites of the eyes due to high bilirubin levels, reflecting liver damage.

In the sylvatic (wild) transmission cycle, the yellow fever virus circulates between mosquitoes of the genera _Haemagogus_ and _Sabethes_ and monkeys. Humans are considered incidental hosts in the sense that people are infected only if they happen to live or work in tropical forests or travel on land through such areas. In the urban transmission cycle, the virus is transmitted to humans (the main host in this case) by the mosquito _Aedes aegypti_.

Yellow fever was endemic in the South and Southeast of Brazil in the early 20th century. Urban transmission has been eradicated thanks to vaccination and action against _Ae. aegypti_ breeding sites.

In the last 2 decades, transmission to humans has occurred outside the Amazon region, where yellow fever is still endemic. Cases have been reported in humans and monkeys in Bahia, Goias, Minas Gerais, Sao Paulo, Parana, and Rio Grande do Sul [states].

Since late 2016, the disease has spread faster and farther, reaching the Atlantic Rainforest biome, with all its extraordinary biodiversity, which includes many species of monkey. Yellow fever had not occurred in these areas for decades.

In search of the yellow fever virus, Cunha and her group investigated samples of brain, liver, and spleen tissue from dead monkeys found by state public health workers and compulsorily sent for analysis to IAL, the state reference laboratory. Samples from 430 dead monkeys were tested between July 2016 and March 2017. Most were _Alouatta_, _Callithrix_, and _Sapajus_, but there were some specimens of black-fronted titi (_Callicebus nigrifrons_) and golden lion tamarin (_Leontopithecus rosalia_), an endangered species.

Investigation in search of the yellow fever virus was carried out in each one of the species. The published study contributes to a better understanding of the biotic pathways involved in the virus's spread from the Amazon to the Southeast. "The study describes the evolution of the virus in different species. The disease is milder in capuchins than in howler monkeys and marmosets," Sabino said.

Not all the dead monkeys sent to IAL died from yellow fever. "Some had been run over and others electrocuted, for example," Cunha said. "The protocol requires analysis by the reference lab of tissue samples from all dead monkeys found, whatever the circumstances."

The presence of the virus was ruled out in most cases, and even in the minority in which it was confirmed, it was not always possible to be sure that death was due to yellow fever. The disease is practically a death sentence for howler monkeys. Marmosets are susceptible but do not always die. Capuchins are considered resistant.

By mid-2017, the epidemic that began in the north of Sao Paulo state in 2016 had spread to the Campinas region, not far from the state capital. "Yellow fever virus hadn't circulated in Campinas since the early 20th century," Cunha said.

The 1st infected monkey was confirmed by IAL in July 2016. It was a capuchin from the Ribeirao Preto region. The species is resistant, so the cause of death was not reported as having been caused by yellow fever, although the virus was found in its tissue.  "The animal came into contact with the pathogen via a mosquito bite but died from other causes. We wanted to find out if capuchins were acting as natural reservoirs of the virus precisely because they're resistant," Cunha said.

Yellow fever virus was found in 67 out of the 430 samples analyzed by Cunha and colleagues at IMT-USP; 30 were from howler monkeys, 9 from marmosets, and 7 from capuchins. The rest were from monkeys of unidentified genera.  "In these 21 cases, the material didn't indicate the genus, but we suspect they were _Alouatta_ owing to the high viral loads in the tissues analyzed," Cunha said.

40-year-old strain
------------------
The researchers isolated the virus from each of the 67 confirmed samples, sequenced the genomes, and compared the genomes with those (available online) of viruses from the outbreaks of yellow fever that occurred between 1980 and 2015 in Brazil and neighboring countries.

They discovered that the strain responsible for the current epidemic originated in Venezuela and in Roraima state and Para State in Brazil. This is in line with prior research suggesting that the 2016-17 epidemic began in the North region and spread to the Southeast by means of a long and continuous sylvatic cycle involving mosquitoes and monkeys.

The results of the study reveal an evolutionary journey of sizable proportions in both time and space. In 1980, yellow fever virus was endemic in Para. In 2000, it reached Mato Grosso do Sul, Goias, and Minas Gerais in the Center-West. By 2004, it had crossed into Venezuela, and by 2009, it had reached Trinidad and Tobago in the Caribbean. In 2010, it was present in Roraima in the [Brazilian] far North, while one strain was found in Rio Grande do Sul in the far South. The virus arrived in Sao Paulo state in 2013.

The molecular analyses performed by Cunha and colleagues showed that the virus was fully disseminated in most Brazilian states and in Suriname by 2017.

Other researchers at IAL and IMT-USP are now conducting similar studies involving the dead monkeys collected in Sao Paulo State during the 2nd wave of the epidemic, in July 2017-June 2018, and during the 3rd wave, which began in July 2018 and will fizzle out this year [2019] with the end of the rainy season and the advent of winter, when the mosquitoes practically stop reproducing.

Depending on the results of these forthcoming studies, it may be possible to determine whether the current epidemic in Sao Paulo state is on the wane. Alternatively, despite mass vaccination the virus could still be spreading through the monkey population and fresh outbreaks may be in the offing.
========================
[Reference
---------
Cunha MS, da Costa AC, de Azevedo Fernandes NCC, et al. Epizootics due to yellow fever virus in Sao Paulo state, Brazil: viral dissemination to new areas (2016-2017). Sci Rep. 2019; 9(1): 5474. doi: 10.1038/s41598-019-41950-3;  <https://www.nature.com/articles/s41598-019-41950-3>

The report above provides a fascinating account of the recent yellow fever (YF) outbreaks and traces the movement of the virus in Brazil over time. Fortunately, in none of the widely dispersed outbreaks were there any reports of urban (people-_Aedes aegypti_-people) transmission of YF virus.

The Brazil Ministry of Health has embarked on an ambitious effort to vaccinate everyone, starting with areas of highest risk. Although that should eliminate human cases, it will not affect the sylvan (forest) cycle involving non-human primates. Meanwhile, human YF cases continue to occur in several states in Brazil this year (2019) (See Yellow fever - Americas (09): Brazil, official summary http://promedmail.org/post/20190627.6541056). An official 8 Jun 2019 report stated that confirmed human yellow fever cases were registered in the states of Sao Paulo (68 cases), Parana (13), and Santa Catarina (1) this year (2019). Most of the cases were rural workers or those exposed in forested areas. The 1st case of yellow fever was confirmed in Santa Catarina state. Cases in non-human primates continue to be reported also. Confirmed epizootics in non-human primates were registered in Sao Paulo (13 cases), Rio de Janeiro (1), Parana (32), Para (1), and Santa Catarina (1). Most of the confirmed epizootics were registered in the southern region (69%; 33/48) with the majority of the epizootics occurring in Parana state.

Continued YF surveillance will be essential to track YF movement in nature over time. - ProMED Mod.TY]

[Maps of Brazil:
<https://www.mapsland.com/maps/south-america/brazil/large-brazil-regions-map.jpg>
and <http://healthmap.org/promed/p/6>]
Date: Fri, 14 Jun 2019 18:27:56 +0200
By Rosa SULLEIRO

Sao Paulo, June 14, 2019 (AFP) - A nationwide strike called by Brazil's trade unions disrupted public transport and triggered road blocks in parts of the country Friday, ahead of protests against far-right President Jair Bolsonaro's pension reform.   Hours before the opening match of the Copa America in Sao Paulo, some metro lines in the country's biggest city were paralyzed as professors and students also prepared to take to the streets over the government's planned education spending cuts.    It will be the latest mass demonstration against Bolsonaro since he took office in January, but the timing could not be worse for the embattled president as Brazil prepares to play Bolivia in South America's showcase football tournament.

Bolsonaro was expected to attend the opener at Morumbi stadium where police sharpshooters will be deployed as part of increased security for the competition.    One of Brazil's main trade unions estimated 45 million workers had taken part in the strike.   Some 63 cities had been affected by the stoppage, with more than 80 cities recording demonstrations, G1 news site said.   The number of protesters is expected to balloon in the afternoon with demonstrations planned in Brazil's major cities.   Protesters have already blocked some roads in several cities, including Rio de Janeiro and Sao Paulo, where G1 said police had used tear gas to disperse demonstrators and clear the streets.   Brazilians were divided over the partial strike.   "This current government wants to destroy everything that we built decades ago so that's why I'm in favor (of the strike) and I am fighting against social inequality," Vania Santos, 49, told AFP in Rio.    In Sao Paulo, Flavio Moreira opposed the stoppage, however, saying it "hurts the commercial part" of the city.

- Pension savings cut -
Bolsonaro's proposed overhaul of Brazil's pension system -- which he has warned will bankrupt the country if his plan is not approved -- is seen as key to getting a series of economic reforms through Congress.    But the changes, including an increase in the retirement age and workers' contributions, have faced resistance from trade unions and in the lower house of Congress, where Bolsonaro's ultraconservative Social Liberal Party has only around 10 percent of the seats.    A pared-back draft of the reform presented to Congress on Thursday -- which reduces expected savings from 1.2 trillion reais ($300 billion) in 10 years to around 900 billion reais -- did little to appease union leaders, who vowed to go ahead with the shutdown.   Such savings are seen as vital to repairing Brazil's finances and economy, which were devastated by a 2015-2016 crisis.

Economy minister Paulo Guedes, who is spearheading the government's reform agenda, has threatened to resign if the bill is not passed or is watered down significantly.   It caps a tumultuous six months for Bolsonaro, who has seen his popularity nosedive as he struggles to push his signature reform through a hostile Congress and keep Latin America's biggest economy from sliding back into recession.   More than 13 million people are unemployed, the latest data shows, with a record number giving up looking for a job.     Fighting between military and far-right factions of Bolsonaro's government has fueled chaos in his administration where his sons and right-wing writer and polemicist Olavo de Carvalho wield enormous influence.   Bolsonaro sacked his third minister on Thursday -- retired general Carlos Alberto dos Santos Cruz, who had been the government secretary and seen as a moderate voice.   That came on the same day Bolsonaro broke his silence to defend Justice Minister Sergio Moro, who has been accused of wrongdoing while serving as a judge in the sprawling Car Wash anticorruption investigation.
Date: Mon 3 Jun 2019
Source: Fit for Travel [edited]
<https://www.fitfortravel.nhs.uk/news/newsdetail.aspx?id=23514>

According to the Brazilian Ministry of Health, there have been 81 cases of yellow fever, including 14 deaths, in the country between 1 Jan and 14 May 2019. Most cases have been confirmed in Sao Paulo (68), with Parana (12) and Santa Catarina (1) also reporting cases.

Nearly all of Brazil is at risk of yellow fever transmission.

Advice to travellers:
- There is a widespread risk of yellow fever in Brazil.

- The World Health Organisation recommends the yellow fever vaccine for travellers to areas at risk of yellow fever (including all of Sao Paulo state and Sao Paulo city) unless contraindicated. Vaccination is advised for all of Parana, Santa Catarina, and Rio Grande do Sul.

- The most recent yellow fever risk map of Brazil is shown here:
<https://ecdc.europa.eu/en/publications-data/yellow-fever-distribution-and-areas-risk-brazil>.

- A traveller's risk of yellow fever is determined by their general risk assessment (e.g., country visited, length of stay, city or rural, activities, etc.).

- Mosquito-bite-avoidance rules should be adhered to at all times; the mosquito that spreads yellow fever bites predominantly during the day.
====================
[As has been noted frequently in previous ProMED-mail posts, yellow fever virus is endemic in Brazil and several other South American countries that have tropical forests where the sylvan (forest) transmission cycle is maintained. So far, in Brazil, the sylvan cycle has not spilled over to urban and suburban areas where _Aedes aegypti_ populations are abundant. Currently, vaccination is the best preventive measure available. The risk of adverse effects due to the vaccine is small, approximately one in 1 million. Yellow fever is a serious disease with a case fatality rate of approximately 30% and a potential for rapid spread in an urban situation with a population with low vaccination coverage and abundant mosquito vectors. - ProMED Mod.TY]

[Maps of Brazil:
<https://www.mapsland.com/maps/south-america/brazil/large-brazil-regions-map.jpg>
and <http://healthmap.org/promed/p/6>]
Date: Fri 31 May 2019
Source: G1 [in Portuguese, trans. ProMED Corr.SB, abridged, edited]
<https://g1.globo.com/pa/santarem-regiao/noticia/2019/05/31/paciente-de-ruropolis-da-entrada-no-hms-com-suspeita-de-raiva-humana.ghtml>

The epidemiology department of the Santarem public health network in western Para is investigating a case of suspected human rabies in a patient who arrived in the city on Thursday night [30 May 2019) from Ruropolis, in Para state.

The patient, a boy only 9 years old, who came from Ruropolis with a referral to TOD (treatment out of domicile) is hospitalized at the Municipal Hospital Dr Alberto Tolentino Sotelo (HMS/Santarem Municipal Hospital). Due to the suspicion of human rabies, the child was placed in an isolation room, where he is receiving medication and going through collection of material for [laboratory] examination.

Through a notice, the Municipal Hospital reported that the epidemiology team at HMS, led by 2 infectious diseases experts, is monitoring the case. Among possible diseases, human rabies is suspected.

Blood, and saliva tests are in the process of being collected and will be sent to the authorized laboratory in Belem. The results should arrive the next week [week of 3 Jun 2019].

Also according to the notice, the clinical picture of the patient is serious. He is intubated in the unit's isolation room.
=======================
[As my ProMED-Port colleague RNA commented this account lacks any information on how this boy might have been exposed and when, when did his symptoms start, and whether he is receiving the appropriate post-exposure immune serum and vaccine. Treatment of human rabies cases once symptoms have started is difficult and rarely successful though latterly, with better knowledge, there have been successes.

HealthMap/ProMED-mail map of Brazil:
<http://healthmap.org/promed/p/65112>.

Ruropolis is a municipality in the state of Para in the northern region of Brazil. The municipality contains part of the Trairao National Forest, in which logging is permitted subject to a management plan. It also holds part of the Tapajos National Forest, a 549,067 hectares (1 356 770 acres) sustainable use conservation unit created in 1974 (<https://en.wikipedia.org/wiki/Rur%C3%B3polis>). This amount of woodland raises the possibility that this boy, if he has rabies, was infected by a bat. Bat rabies is common in Brazil. Of course it could have been from a rabid dog. - ProMED Mod.MHJ]

[More information on the results of testing and epidemiologic information such as route of transmission and location of exposure would be greatly appreciated. - ProMED Mod.MPP]
Date: Fri 24 May 2019
Source: Virologica Sinica [edited]
<https://doi.org/10.1007/s12250-019-00129-w>
<https://link.springer.com/article/10.1007%2Fs12250-019-00129-w>

[Concern about yellow fever (YF) vaccine availability has been increasing following the large outbreak in Angola and the Democratic Republic of the Congo and more recently in Brazil. Because YF vaccine supplies were not adequate to provide full 0.5 ml doses during those outbreaks, a 1/5th fractional dose was used. The abridged report below reviews the situation and proposes measures to be taken. - ProMED Mod.TY]

Daniel R Lucey, Kristen R Kent. Boosting global yellow fever vaccine supply for epidemic preparedness: 3 actions for China and the USA. Virol Sin. (2019). <https://doi.org/10.1007/s12250-019-00129-w>

In 2016, 2 unprecedented events occurred regarding yellow fever flavivirus infection and vaccine. 1st, in China, 11 persons were diagnosed with yellow fever virus after being infected while working in Angola and returning to China in March-April 2016 (WHO 2016a; Wang et al, 2016; Chen et al, 2016). No transmission within China occurred (Chen and Lu 2016). These were the 1st persons anywhere in Asia known to have laboratory-documented yellow fever infection. 2nd, a global shortage of yellow fever vaccine resulted in the 1st-ever use of a fractional (1/5th) normal dose of yellow fever vaccine anywhere in the world when it was given to 7.5 million people in Kinshasa, Democratic Republic of the Congo (DRC) in August 2016 (Monath et al. 2016; WHO 2016b).
 
These 2 events catalyzed multiple reports about the potential risk and implications of yellow fever epidemics occurring for the 1st-time ever in China or anywhere else in Asia where the _Aedes aegypti_ vector for yellow fever and dengue exists - for example, India, Pakistan, Thailand, Indonesia and beyond (Wasserman et al, 2016: Baumgaertner 2016; The Economist 2016; Schlagenhauf and Chen 2017; Wilder-Smith and Leong 2017; Lucey and Donaldson 2017; Brey et al, 2018; Shearer et al, 2018; Musso et al, 2018; Wilder-Smith and Massad 2018; Brent et al, 2018). Moreover, this fractional dosing of vaccine in Kinshasa in 2016 signified that if additional outbreaks occurred soon after anywhere in the world - for example, Africa, Latin America or Asia, then shortages of full-dose vaccine would likely occur as well.

WHO created the 1st-ever "Global strategy for eliminating yellow fever epidemics (EYE) 2017-2026" program in September 2016 (WHO 2016d). This program estimated that 1.38 billion doses of yellow fever vaccine would be required to eliminate yellow fever epidemics from endemic areas in sub-Saharan Africa and in Latin America and the Caribbean (WHO 2016d). This projected 1.38 billion doses of vaccine did not include any doses for Asia, a continent with no prior yellow fever transmission or vaccination campaigns, and, therefore, immunologically-susceptible to yellow fever epidemics.

Of concern, in Brazil throughout 2018 and into 2019, a YF vaccine shortage required use of the fractional (1/5th) dose involving at least 21 million persons (PAHO 2018, 2019). Due to their national vaccine shortage, Brazil was no longer able to export YF vaccine, as they had done for use in Angola and DRC in 2016. Of note, only the Brazilian vaccine has been used for fractional dosing. Thus, vaccine being used outside of Brazil - for example, sub-Saharan Africa, in 2018 was full-dose vaccine.

Actions to boost YF vaccine supply by China and the USA:

We advocate for 3 actions to be taken by the USA and China to help boost global supply of YF vaccine and increase epidemic preparedness and response. 1st, both nations would work with the WHO to have their YF vaccines prequalified. Thus, their vaccines could be used outside their own borders as part of the international stockpile of YF vaccine as traditionally administrated by the WHO, UNICEF and other members of the multi-partner International Coordinating Group (ICG). 2nd, production of this vaccine would be sharply scaled up by both countries. These vaccines could be made available nationally, regionally, and globally through the ICG - for example, to help stop and prevent epidemics anywhere in the world. 3rd, clinical studies would be coordinated with the WHO to assess the efficacy and safety of fractional dosing using 1/5th normal dose and, if needed, even a 1/10th dose.
=====================
[Readers interested in the YF vaccine situation are encouraged to read the full report available at the above URL. Unfortunately, it is available only through subscription or purchase. - ProMED Mod.TY]
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