Research: Monoclonal Antibodies Against Nipah

Geographic Range of Nipah, Hendra, and fruit bats of the Pteropodidae family – Credit WHO

 

 

# 8782

 

In 2011, in  NIH: Investigating A Potential Treatment For Hendra & Nipah Viruses we looked at research using the human monoclonal antibody (hmAb) m102.4 to protect African green monkeys (AGMs) against a Hendra Virus challenge. Twelve subjects were infused with a 100-mg dose of m102.4 beginning at either 10, 24, or 72 hours after infection and again about 48 hours later.

 

All twelve primates that received the antibodies survived, while all control subjects died by day 8.

 

The results were so promising, Australian health officials requested m102.4 for emergency use in a woman and her 12-year-old daughter who had been exposed to a horse with the Hendra virus in 2010. Both the woman and child survived and showed no side effects from the treatment (cite).

 

Similarly, in 2009, research published in PLoS Pathogens  illustrated its protective effect against Nipah in ferrets (see A Neutralizing Human Monoclonal Antibody Protects against Lethal Disease in a New Ferret Model of Acute Nipah Virus Infection).

 

Monoclonal antibodies would not work like a vaccine and confer long-term protection.  Instead, a single injection (or series of injections) is hoped to serve as a treatment, or to work as a temporary (several week) prophylaxis.

 

While the research above was promising, most of these studies involved starting treatment before, or just shortly after, infection, an unrealistic scenario for most therapeutic uses.  

 

Today, we’ve a new study – conducted by University of Texas Medical Branch at Galveston, the Uniformed Services University of the Health Sciences at Bethesda, MD and three NIH Labs (2 at Hamilton, MT & 1 Frederick, MD) -  that shows impressive results (on non-human primates, anyway), even when therapy is started 5 days post exposure.

 

 

Science Translational Medicine

INFECTIOUS DISEASE

Therapeutic Treatment of Nipah Virus Infection in Nonhuman Primates with a Neutralizing Human Monoclonal Antibody

Thomas W. Geisbert¹,²,*,†, Chad E. Mire¹,²,*, Joan B. Geisbert¹,², Yee-Peng Chan³, Krystle N. Agans¹,², Friederike Feldmann⁴, Karla A. Fenton¹,², Zhongyu Zhu⁵, Dimiter S. Dimitrov⁵, Dana P. Scott⁴, Katharine N. Bossart⁶, Heinz Feldmann⁷ and Christopher C. Broder³,†

Abstract

Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes severe and often fatal disease in pigs and humans.

There are currently no vaccines or treatments approved for human use. Studies in small-animal models of NiV infection suggest that antibody therapy may be a promising treatment. However, most studies have assessed treatment at times shortly after virus exposure before animals show signs of disease.

We assessed the efficacy of a fully human monoclonal antibody, m102.4, at several time points after virus exposure including at the onset of clinical illness in a uniformly lethal nonhuman primate model of NiV disease.

Sixteen African green monkeys (AGMs) were challenged intratracheally with a lethal dose of NiV, and 12 animals were infused twice with m102.4 (15 mg/kg) beginning at either 1, 3, or 5 days after virus challenge and again about 2 days later. The presence of viral RNA, infectious virus, and/or NiV-specific immune responses demonstrated that all subjects were infected after challenge.

All 12 AGMs that received m102.4 survived infection, whereas the untreated control subjects succumbed to disease between days 8 and 10 after infection. AGMs in the day 5 treatment group exhibited clinical signs of disease, but all animals recovered by day 16. These results represent the successful therapeutic in vivo efficacy by an investigational drug against NiV in a nonhuman primate and highlight the potential impact that a monoclonal antibody can have on a highly pathogenic zoonotic human disease.

Copyright © 2014, American Association for the Advancement of Science

 

Now that this hmAb has been shown effective against the Nipah virus in non-human primates, researchers hope they may have the basis for what will eventually become a viable treatment for these deadly viruses.  For a bit more background, the following is an excerpt from a press release from the University of Texas Medical Branch.

 

Researchers one step closer to countering deadly Nipah virus

June 25, 2014

Human antibody therapy successfully combats virus five days after infection

An interdisciplinary research team from the University of Texas Medical Branch at Galveston, the Uniformed Services University of the Health Sciences and three groups within the National Institutes of Health reports a new breakthrough in countering the deadly Nipah virus. The human monoclonal antibody known as m102.4 is the first effective antiviral treatment for Nipah that has the potential for human therapeutic applications.

Nipah and the closely related Hendra virus are highly infectious agents that emerged from Pteropid fruit bats in the 1990s, causing serious disease outbreaks in a variety of domestic animals and humans in Australia, Malaysia, Singapore, Bangladesh and India. Recent Nipah outbreaks have resulted in acute respiratory distress syndrome and encephalitis, person-to-person transmission and greater than 90 percent fatality rates among people. These properties make both Nipah and Hendra viruses a concern to human and livestock health.

(Continue . . . )

For some other blogs on the development, and testing of monoclonal antibodies, you may wish to revisit:

 

• In 2009 in Research: Monoclonal Antibodies Against Influenza researchers at the Dana-Farber Cancer Institute (Dana-Farber), Burnham Institute for Medical Research (Burnham) and the Centers for Disease Control and Prevention (CDC) announced the identification of human monoclonal antibodies (mAb) that work against a wide range of influenza viruses, including the H5N1 bird flu virus.
• And in 2010, in Monoclonal Antibodies Revisited, we looked a Korean company (Celltrion) working on Human Monoclonal Antibodies (moAb) that are designed to work against a wide variety of influenza viruses. 

 

CIDRAP:Two MERS Antibody Studies

Photo Credit NIAID

 

 

# 8546

 

 

Last night CIDRAP News published a report by Lisa Schnirring on a pair of human antibody studies released yesterday looking at potential treatments for the MERS coronavirus.  The studies appear in Science Translational Medicine and PNAS, and Lisa does a terrific job summarizing them.

 

Two MERS antibody studies may help quest for treatment

Lisa Schnirring | Staff Writer | CIDRAP News

|

Apr 28, 2014

Amid a surge of MERS-CoV (Middle East respiratory syndrome coronavirus) cases, two research teams today—one based at Harvard University and the other in China—said they have identified antibodies against the novel virus, the first of many steps toward developing a treatment against the disease.

 

The two teams used different search strategies and identified different types of antibodies, but their target was the same: preventing the spike-shaped protein on the surface of MERS-CoV from binding to receptors on the surface of cells that line human airways.

 

MERS-CoV causes a respiratory infection that can lead to severe pneumonia and kidney failure. The disease is fatal for more than 40% of patients infected, and so far there is no treatment or vaccine.

(Continue . . . )

 

Although promising, as Lisa explained, the identification of potentially useful antibodies against the MERS coronavirus is but the first step towards creating a usable therapy.  Over the past 5 years we’ve looked at several similar studies, including:

 

• In 2009 in Research: Monoclonal Antibodies Against Influenza researchers at the Dana-Farber Cancer Institute (Dana-Farber), Burnham Institute for Medical Research (Burnham) and the Centers for Disease Control and Prevention (CDC) announced the identification of human monoclonal antibodies (mAb) that work against a wide range of influenza viruses, including the H5N1 bird flu virus.
• Similarly, in 2010, in Monoclonal Antibodies Revisited, we looked a Korean company (Celltrion) working on Human Monoclonal Antibodies (moAb) that are designed to work against a wide variety of influenza viruses. 
• In 2011, we looked at NIH: Investigating A Potential Treatment For Hendra & Nipah Viruses which looked at using the human monoclonal antibody (hmAb) m102.4 to protect green monkeys against a Hendra Virus challenge. In 2009 research published in PLoS Pathogens  illustrated its protective effect against Nipah in ferrets.

 

These monoclonal antibodies would not work like a vaccine, which confer relatively long-term protection.  Rather, a single injection is expected to serve as a treatment, or to work as a temporary (several week) prophylaxis.

 

While a hugely promising field of research, the above examples show that isolating a candidate antibody is a long way from having a tested and approved therapy. 

 

We’ve seen  a great deal of optimism expressed by the Saudi government about rapidly developing a vaccine for the MERS coronavirus. While no doubt reassuring to the public, a vaccine is something that most scientist believe will take several years to develop (see Obstacles To A MERS Vaccine). 

 

Although a human antibody therapy might be brought to market sooner, no one should expect they will provide a near-term solution to the MERS problem either.

NIH: Investigating A Potential Treatment For Hendra & Nipah Viruses

 

 

# 5911

 

 

The movie `Contagion’ showed the world how a bat virus could mutate, evolve, and move into the human population. While the movie used a fictionalized MEV-1 virus, bats in some parts of the world are known to carry deadly pathogens, such as the Nipah and Hendra viruses.

 

While human infections with these two viruses have been relatively uncommon, when they have occurred they have proven particularly lethal, with fatality rates exceeding 60%.

 

Nipah was first identified in Malaysia in 1998, where it jumped to local swine herds from bats, and along with infecting hundreds of people, it caused the loss over 100 lives. The virus was then exported via live pigs to Singapore, where 11 more people died.

 

Over the past decade, Nipah has caused a number of small outbreaks across Southern Asia, although the most intense activity has been centered around Bangladesh.

 

The Hendra virus was first isolated in 1994 after the deaths of 13 horses and a trainer in Hendra, a suburb of Brisbane, Australia. A stable hand, who also cared for the horses, was hospitalized, but survived.

 

Another outbreak took place in MacKay, 1000 km to the north of Brisbane, the previous month. Two horses died, and the owner was hospitalized several weeks later with meningitis.

 

He recovered, but developed neurological symptoms and died 14 months later.

 

Subsequent studies have showed a high prevalence of the newly identified Hendra virus in Pteropid fruit bats (flying foxes) in the region.

 

Nipah/Hendra Virus & Fruit Bat Home Range – WHO

 

Although very similar, unlike Hendra, the Nipah virus has been shown to be transmissible from human-to-human. Like all viruses, both have the potential to mutate and evolve - and over time - become better adapted to their hosts.

 

According to the World Health Organization there are currently no effective treatments for either of these diseases (see here and here), but according to a new study just published in the journal Science Translational Medicine, there is hope that may change.

 

The study is called:

 

Sci Transl Med 19 October 2011:
Vol. 3, Issue 105, p. 105ra103
Sci. Transl. Med. DOI:

10.1126/scitranslmed.3002901

A Neutralizing Human Monoclonal Antibody Protects African Green Monkeys from Hendra Virus Challenge

Katharine N. Bossart, Thomas W. Geisbert, Heinz Feldmann, Zhongyu Zhu, Friederike Feldmann, Joan B. Geisbert, Lianying Yan, Yan-Ru Feng, Doug Brining, Dana Scott, Yanping Wang, Antony S. Dimitrov, Julie Callison, Yee-Peng Chan, Andrew C. Hickey, Dimiter S. Dimitrov, Christopher C. Broder,† and Barry Rockx

 

The NIH – which supported this research – issued a press release yesterday afternoon describing this study:

 

Embargoed for Release
Wednesday, October 19, 2011
2 p.m. EDT

Antibody treatment protects monkeys from Hendra virus disease

NIH-supported group exploring whether protection extends to Nipah virus disease

A human antibody given to monkeys infected with the deadly Hendra virus completely protected them from disease, according to a study published by National Institutes of Health (NIH) scientists and their collaborators. Hendra and the closely related Nipah virus, both rare viruses that are part of the NIH biodefense research program, target the lungs and brain and have human case fatality rates of 60 percent and more than 75 percent, respectively. These diseases in monkeys mirror what happens in humans, and the study results are cause for hope that the antibody, named m102.4, ultimately may be developed into a possible treatment for people who become infected with these viruses.

 

In May 2010, shortly after the NIH study in monkeys successfully concluded, Australian health officials requested m102.4 for emergency use in a woman and her 12-year-old daughter. They had been exposed to Hendra virus from an ill horse that ultimately was euthanized. Both the woman and child survived and showed no side effects from the treatment.

(Continue . . . )

 

 

The human monoclonal antibody (hmAb) m102.4 has been the object of Hendra-Nipah research for a number of years. In 2009 research published in PLoS Pathogens  illustrated its protective effect against Nipah in ferrets.

 

A Neutralizing Human Monoclonal Antibody Protects against Lethal Disease in a New Ferret Model of Acute Nipah Virus Infection

 

 

Now that this hmAb has been shown effective against the Hendra virus in primates, researchers hope they may have the basis for what will eventually become a viable treatment for these deadly viruses.

 

For more on human monoclonal antibodies, and their potential to treat influenza, you may wish to revisit a couple of blogs I wrote in 2009 and 2010:

 

Research: Monoclonal Antibodies Against Influenza

Monoclonal Antibodies Revisited

Monoclonal Antibodies Revisited

 

 

# 4415

 

 

Every few months we seem to see a new press release or news story about some whiz-bang invention, discovery, or experimental drug that promises to revolutionize the way we treat or prevent influenza.   

 

Often these stories are about discoveries that hold genuine promise, but that are still some time away from practical application. 

 

This morning we’ve a press release and some news stories about a Korean company working on Human Monoclonal Antibodies (moAb) that are designed to work against a wide variety of influenza viruses. 

 

This from The Korean Times.

 

New Anti-Influenza Drug Being Developed

By Bae Ji-sook
Staff Reporter

Celltrion has developed a drug based on "human monoclonal antibodies" that can be effective against multiple influenza viruses, the biopharmaceutical company said Tuesday.

 

The company tentatively called the drug a Super Flu-Antibody Therapy.

 

This is the first time a drug effective against multiple viruses has been developed in Korea. Celltrion expects to release the product next year, ahead of major rivals in the U.S. and other countries who have also been successful in developing substances that are effective against one or more viruses.

 

(Continue . . . )

 

 

If all of this sounds a tad familiar, it may be because a little over a year ago researchers at the Dana-Farber Cancer Institute (Dana-Farber), Burnham Institute for Medical Research (Burnham) and the Centers for Disease Control and Prevention (CDC) reported the identification of human monoclonal antibodies (mAb) that worked against a wide range of influenza viruses, including the H5N1 bird flu virus.

 

See Research: Monoclonal Antibodies Against Influenza

 

These antibodies targeted a highly conserved stem region of the H5 hemagglutinin (HA) which prevented the virus’s entry into a cell, and this portion of the virus is consistent across many (but not all) influenza strains.

 

Potentially a `magic bullet’ against influenza, assuming that it works as well (and as safely) in humans as it did in laboratory mice.

 

These monoclonal antibodies would not work like a vaccine, which confer relatively long-term protection.  Rather, a single injection is expected to serve as a treatment, or to work as a temporary prophylaxis.

 

Monoclonal antibodies are viewed by many researchers to hold promise for influenza treatment, but human trials have not been conducted, and substantial uncertainties exist.

 

Celltrion, Inc has released an optimistic sounding press release today on their latest monoclonal antibody research on mice, promising to move forward with clinical trials `as quickly as possible’.  

 

You can read the release at the link below.

 

Successful Development of Broad Spectrum Human Monoclonal Antibodies Against Major Influenza Viruses (H1N1 and H5N1)

 

Even if successfully brought to market in the next few years, monoclonal antibodies are not likely to become a panacea against a pandemic.  These are injectable, short-lived medications that are likely to remain expensive and limited in availability for the foreseeable future.  

 

Regardless of how these clinical trials turn out, or whether monoclonal antibodies prove to be a practical treatment for influenza down the road, this is another important step forward in our understanding of how influenza viruses work.

 

And that, over time, will no doubt pay big dividends.