Tag Archives: vaccine

Universal Meningitis B vaccine nears approval by European regulators – thank the mice (and the scientists)!

Bacterial meningitis is an infection of the fluid that is found in the spinal cord and surrounding the brain that affects thousands of people – usually children or young people – every year and can result in brain damage, hearing loss, or learning disability. In about 10% of cases the infection is fatal. One of the most common causes of bacterial meningitis is infection by Neisseria meningitides, and while vaccines have been developed against some serotypes of N. meningitides, but so far no vaccine has been produced that can provide broad protection against N. meningitides serotype B (Meningitis B), which is responsible for most cases of bacterial meningitis in Europe. A major problem has been that there are many different strains of Meningitis B, and until now vaccines made against it have only protected against single specific strains, so that their usefulness has been very limited.

Last weekend we learned that a new “Universal” vaccine that protects against a  broad range of Meningitis B strains  the has been given a ‘positive opinion’ by the European Medical Agency’s Committee for Medical Products and is now expected to be granted a license within 2-3 months. The Bexsero vaccine – called 4CMenB during its development – was developed by Novartis and has been hailed as the “biggest leap forward in the field” in 30 years by the charity Meningitis UK, and if added to the vaccination schedule will for first time enable babies and young people to be vaccinated so that they are protected against Meningitis B strains for many years to come.

Studies in mice played a crucial role in the development of the new Meningitis B vaccine. Image courtesy of Understanding Animal Research.

At this point some of our readers may be wondering why this all sounds a little familiar. Never fear, there is a good reason for this.

Bexsero was made by adding to an experimental recombinant antigen vaccine named rMenB – a vaccine that had already provided a high degree of protection against a wide range of Meningitis B strains in earlier trials – the outer membrane protein that had been used in a vaccine against a specific strain of Meningitis B that was responsible for an outbreak in New Zealand.  The resulting multicomponent vaccine provided an even higher degree of protection against multiple Meningitis B strains, particularly in infants, making it more suitable for use in large-scale preventative vaccination programs (1).

But where did rMenB come from? For that we have to take a look back at a post I wrote for this blog in 2008 entitled “A vaccine against Meningitis B”, which describes the key role played by experiments in mice and rats during the development of this innovative vaccine:

The development of the new vaccine is also noteworthy because of how it was done. Vaccine development relies on identifying parts of the bacterium known as antigens that can act as targets for the immune system. Rather than using the usual method of attempting to isolate bacterial protein that might act as antigens the Novartis team led by Dr. Mariagrazia Pizza adopted a “reverse vaccinology” approach where they searched the Neisseria meningitidis genome for genes that encoded proteins that might be useful antigens. They identified over 300 potential antigens, and the next step was to screen these for their ability to stimulate the immune system to produce antibodies that kill bacteria in vitro. This required an intact functioning mammalian immune system, so the researchers used mice.

The mice were injected with candidate antigens and later antibodies were harvested from the mice and tested for their bactericidal activity against three distinct strains of Neisseria meningitidis, identifying twenty eight antigens that induced the production of bactericidal antibodies. However none of these 28 antigens were potent enough to be used alone in a universal vaccine, so the researchers next assessed various combinations of the most promising antigens. A vaccine containing 5 antigens was found to induce the production of antibodies that had excellent bactericidal activity against all three strains of Neisseria meningitidis. The multicomponent vaccine was then tested against a panel of 85 type B Neisseria meningitidis strains that represent the global diversity of the bacterium, and was found to be effective against almost all strains, especially the most lethal strains. To check that the bactericidal activity in vitro correlated to an ability to prevent disease rats which had been infected with Neisseria meningitidis were treated with serum containing antibodies from vaccinated mice. Rats that were treated with serum were fully protected, a result that provided good evidence that the multicomponent vaccine works.”

It’s great to see how this work has resulted in an effective vaccine that will soon protect thousands of people from disability and death, as Meningitis Trust Chief Executive Sue Davie noted in a statement earlier this week:

Vaccines are the only way to protect against bacterial meningitis and given the successes of the other meningitis vaccines already in use here in the UK, it’s hard not to be really excited at the news. We realise there is still a way to go before it is available, but this is a major step forward in protecting against MenB.”

It is worth noting that the successful meningitis vaccines already in use in the UK include the Hib polysaccharide-protein conjugate vaccine, which has almost eliminated meningitis due to infection with the Haemophilus influenzae type B bacteria, once the major cause of meningitis in babies and young children.  Needless to say animal research played a crucial role in the development of this vaccine against Haemophilus influenzae type B (2,3). Soon Bexsero may have an equally dramatic impact on Meningitis B, and mark another success against this devastating illness.

Paul Browne

1)      Toneatto D, Ismaili S, Ypma E, Vienken K, Oster P, Dull P. “The first use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in humans.” Hum Vaccin. 2011 Jun;7(6):646-53. PubMed: 19622040

2)      Kelly DF, Moxon ER, Pollard AJ. ”Haemophilus influenzae type b conjugate vaccines.” Immunology. 2004 Oct;113(2):163-74. PubMed: 15379976

3)      Schneerson R, Barrera O, Sutton A, Robbins JB “Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates.” J Exp Med. 1980 Aug 1;152(2):361-76. PubMed: 6967514

The end of cancer? A personal view.

My husband died of stage 4 metastatic esophageal cancer on August 19, 2011.

I have been an advocate for biomedical research, specifically involving animals, for decades. I go to work each and every day supporting researchers involved with discovering new cures or treatments. I dedicate time outside of those duties to promote education regarding the use of animals in such research. I want people to be able to make up their own minds free of rhetoric and sound bites empty of any real information. Research is part of who I am.

All of this became intensely personal for me, more so than it was, in February of 2010 when my husband was diagnosed. They did not need to explain to me how serious his diagnosis was. I already knew. I knew it was going to be a tough battle but he was a fighter. He was not ready to leave me or his daughters or the life we built. Not now. Not to cancer. No way.

He remained a fighter until his very last day on this earth. In our last conversation he told me cancer had only taken his body but he was still free and he will be waiting for me when the time comes for me to shed my body too. I still work in the same hospital where all his treatments had taken place and I eat at the same cafeteria where I bought all his food when he was in the hospital. I still see some of his caregivers in the hallways and they always ask me how I am. They are very caring people and I am sure each and every one of them would applaud an end to cancer. I know I would. I am pretty sure everyone that has been touched by this horrible disease would love to see an end to it, just as I am sure people were very happy to see an end to polio or small pox.

On Monday, author Sharon Begley published an article in The Daily Beast entitled “Could This Be The End Of Cancer?”outlining some of the new developments in the fight against cancer, particularly using vaccines. It is detailed but easy to read, and it was nice to see more information on some of the treatments my husband received. Research for cancer and many other diseases go on each and every day by thousands of people. Some of those people remember what life was like before the current vaccines we take for granted were widely used. In reading the evaluation results for the polio vaccine, you can see how many children were affected and see pictures of them in iron lungs. My generation has never known a friend confined to one of those thanks to those who continued the research that lead to the vaccine. The mortality rates for small pox were up to 35% and yet according to the WHO this disease was eradicated in 1979, thanks to those who developed the first vaccine. I doubt anyone who was born after 1975 could really tell you what small pox looked like without looking it up thanks to those who continued to search and refine the current vaccine.

Immunotherapy – developed through animal research – offers new hope to patients with Chronic Lymphocytic Leukemia, and is an example of recent advances in cancer treatment discussed by Sharon Bagley

Without research, both with animals and humans, or those dedicated to searching for answers, no cures are possible. Will we see vaccines for all cancers in the next 30 years? No one can answer that, just like no one can give you a date when the human race will finally stop wars. But does that mean we should stop looking? Stop striving? Stop hoping for a cure? Absolutely not. Polio and small pox are simple diseases if compared with the complexity of cancer. It is going to take lots of time, lots of man hours and a lot of dedication from a lot of people to finally put this monstrous disease in the “eradicated” file.

It is also going to take a lot of money. On Ms. Begley’s article page is a comment regarding this money. The poster states:

This is a nice read, but … this will never happen. At least not in our life time as Cancer has become a big business. I am a ovarian 3 cancer survivor and I can tell you that there would be a lot of people out of work if there ever was a cure. The Government would fail. “

Do you suppose she is happy about the treatments she received for her disease that has extended her life? Would she reject a vaccine in favor of current treatments if her cancer was to reappear? Somehow I think she would take the easier treatment.

Is finding cures and treatments expensive? You bet it is. Is funding from the government and charities vital to this research? Absolutely. Without it we would not be able to hire the scientists, the biologists, the doctors or the nurses who work tirelessly each and every day, not only to find a cure, but to make every day in the life of a cancer patient the best it can be. And believe me, we are not a rich bunch. We shop at dollar stores and check the clearance section too just like so many people do in our current economic state.

However…

Do you think any one of us would give up their job to find that cure tomorrow? I know I would. In a heartbeat. It is too late to save my husband. But if I could save everyone else, every kid, mother, father, wife, husband and friend, from having to go through what I just went through, I would collect my last paycheck today. Right now.

But until that cure happens, we are going to come to work and continue searching, perfecting, refining and aiming for that day to come. And it will come.

Pamela Bass

Mice and macaques pave the way for effective HIV vaccines

There is encouraging news this week on the prospects for an effective vaccine against HIV. A  research team led by Professor Mariano Esteban at the Spanish Superior Scientific Research Council (CSIC) have announced that the vaccine MVA-B elicited a persistent immune response against HIV in  85% of volunteers in a phase 1 clinical trial. MVA-B is a therapeutic vaccine, it is not intended to block infection but rather to keep HIV levels in the body at levels well below those at which the virus can cause illness.

As a CSIC press release published online on EureakAlert! notes the MVA-B vaccine, created by inserting four HIV genes from the B subtype of HIV – the subtype accounting for most HIV infections in Europe and North America – into a vector derived from the Modified Ankara Vaccinia virus (a smallpox vaccine and shown to be safe in both animal studies and extensive human use), notes that:

In 2008, MVA-B already showed very high efficiency in mice as well as macaque monkeys against Simian’s immunodeficiency virus (SIV). Due to it’s high immunological response in humans, Phase I clinic trials will be conducted with HIV infected volunteers, to test its efficiency as a therapeutic vaccine.”

This is indeed true, a 2007 study in mice revealed that the MVA-B vaccine induced a strong immune response , while a paper published in 2008 by the same group demonstrated that a very similar MVA vaccine was able to induce a robust response involving both the HIV-1-specific CD4+ helper T-cells  and CD8+ cytotoxic T cells in Rhesus macaques, and was able to control virus levels in macaques infected with the SHIV 89.6P hybrid virus whereas in unvaccinated monkeys the levels of virus rose and most developed an AIDS-like illness.

There is a question over whether the immune response generated by the MVA-B vaccine will be able to restrict HIV in humans, after all the MRK-Ad5 vaccine which failed to restrict the HIV virus in human trials and the pathogenic SIV MAC239 – considered a better model for HIV infection than SHIV 89.6p – in macaque monkeys had successfully controlled SHIV 89.6P in earlier studies.

Some reassurance on this issue comes from a study at Oregon Health and Science University (OHSU) that was announced earlier this year, where a group led by Dr. Louis Picker used a different vaccine vector – one based on Cytomegalovirus – to elicit a very similar broad immune response , with strong memory T-cell involvement, to that induced by MVA-B, and found that it induced long-term control the highly pathogenic SIV MAC239 strain. This was the highest degree of control demonstrated to date against this SIV strain, and indeed the cytomegalovirus vaccine is one of the first to demonstrate any ability to control SIV MAC239 levels.

Professor Esteban and his colleagues are certainly not resting on their laurels either, further clinical trials of the MVA-B vaccine are planned, to determine whether it can protect against HIV.  In the meantime they are also seeking to improve on this vaccine.  Earlier this year they published a paper in the open-access journal PloS One where they deleted a gene in the MVA vector to yield a new MVA-B  vaccine that showed in mice a substantial increase in the magnitude and breath of the immune response compared with their original MVA-B vaccine, and an even better  memory T-cell response. They now plan to evaluate this improved vaccine in a non-human primate model of HIV infection, and it will be interesting to see if they choose to use a more stringent model of infection such as SIV MAC239 rather than SHIV-89.6P.

Despite the setbacks and disappointments over the past two decades, it is clear from the work being done at the CSIC and OHSU that real progress is being made towards the development of both prophylactic and therapeutic  vaccines against HIV, and it is just as clear that animal research continues to play a vital role in that progress.

Paul Browne

Novartis stands up for animal research

Pharmaceutical companies have traditionally tended to avoid direct involvement in the debate on animal research, even though they and their employees and contractors  are among the more frequent targets of animal rights extremism, so I was delighted to see this new video from the leading pharmaceutical company Novartis on YouTube.

That it is Novartis leading the way on this issue should not be too much of a surprise. In 2009 animal rights extremists fire-bombed the house of Daniel Vasella, then CEO of Novartis, during a vicious campaign that also included the theft of his Grandmother’s ashes from her grave.  If the extremists expected Novartis to give in to their demands (to stop dealing with contract research organization Huntingdon Life Sciences) they were to be disappointed, not only did Novartis not cave in to their attacks, but in an interview with USA Today Daniel Vasella spoke of the need for pharmaceutical industry leaders to speak out against animal rights extremists, correctly stressing the need to marshall public support for animal research.

Q: What do you get from confronting enemies? You’re not going to change their minds.

A: You win public support. With that, you can achieve anything. Without public support, you cannot achieve anything.

Q: This Q&A makes no attempt to determine right and wrong in animal testing debate. But aren’t you helping activists by giving them the soapbox they desire?

A: I don’t believe so. It’s my duty as a citizen to speak up when illegal actions take place. Suffering in silence doesn’t help anybody. You have to stand up. You have to fight for something. If everyone remained silent, then the people who are violent would prevail.

- – -

Q: If you were to do it over again, would you do anything differently?

A: I would go public earlier, immediately. We should have done more to engage politicians and the press in making them aware what was going on, because we need the public to understand.

These are messages that everyone involved in biomedical research – not just the CEOs of pharmaceutical companies – should take on board.

Novartis has a good record of developing innovative treatments, and of course this success has depended on – amongst many other methods – basic and translational animal research.  A very good example of this is the broad-coverage meningitis B vaccine Bexsero which is currently under review by the European Medicines Agency, which will, if approved, become the first vaccine to protect against a a broad range of group B Neisseria meningitidis strains responsible for a disease that kills and injures hundreds of mostly young people in the USA every year, and many thousands world-wide. Naturally studies in animals played a critical role in the development of this new vaccine, as I discussed in a post on Speaking of Research in 2008.

This initiative by Novartis is in its infancy, but is a promising sign that while Daniel Vasella may have retired from his position as CEO of Novartis, his enthusiasm for engaging with the public has rubbed off on his former colleagues.

Well done Novartis!

Paul Browne

Albert Sabin and the monkeys who gave summer back to the children.

Albert Sabin has been called “the doctor who gave summer back to the children.”*

Because of his decades of research to develop the oral polio vaccine, children today know nothing of the fear that polio brought to the United States every summer well into the 20th century.  Swimming pools and movie theaters were closed and children were kept inside their homes by frightened parents.  Worldwide, the disease killed millions of people and left legions of others permanently disabled.

Albert Sabin administering the vaccine that saved millions from polio.

We’ve just celebrated the 50th anniversary of the introduction of Dr. Sabin’s vaccine. Estimates suggest that in just its first two years of worldwide use, the vaccine prevented nearly 500,000 deaths and five million cases of polio.  Today, the world is on the brink of realizing Dr. Sabin’s lifetime dream: the eradication of polio from the planet.

The development of the oral polio vaccine required years of extensive research with rabbits, monkeys and rodents.

Animal rights activists long ago seized on a single phrase by Dr. Albert Sabin, and have been using it ever since to try to support their outrageous claim that the developer of the oral polio vaccine(OPV) opposed the use of animals in research.

That phrase, “The work on prevention (of polio) was long delayed by an erroneous conception of the nature of the human disease based on misleading experimental models of disease in monkeys” spoken by Dr. Sabin during a congressional hearing in 1984, has been used in animal rights publications and comments for over two decades.

Dr. Sabin, a member of the Board of Directors of the pro-research Americans for Medical Progress until his death in 1993, spent years working to correct the record.  Here is a letter he wrote to the editor of the Winston Salem Journal, published in 1992.

Winston-Salem Journal

March 20, 1992

The Correct Conclusion

In a recent letter to the Journal (“Misrepresenting Research,” Feb. 20), Dr. Stephen R. Kaufman, the chairman of the Medical Research Modernization Committee, correctly quoted my 1984 testimony before Congress but he drew wrong conclusions from it.  Dr. Kaufman was also wrong when the said “the polio vaccine was based on a tissue culture preparation … not animal experimentation.”

On the contrary, my own experience of more than 60 years in biomedical research amply demonstrated that without the use of animals and of human beings, it would have been impossible to acquire the important knowledge needed to prevent much suffering and premature death not only among humans but also among animals.

In my 1956 paper in the Journal of the American Medical Association (Vol. 162, p. 1589), I stated that during the preceding four years “approximately 9,000 monkeys, 150 chimpanzees and 133 human volunteers were used thus far in studies of various characteristics of different poliovirus strains.”  These studies were necessary to solve many problems before an oral polio-virus vaccine could become a reality.

Albert B. Sabin, M.D.

Washington”

It is true that in the early years of polio research some lines of inquiry eventually proved unsuccessful. An overreliance on a strain of the virus known as the MV strain that had become adapted to survive only in nervous tissue, and the fact that the Rhesus macaque, while a good model for many aspects of polio, cannot be infected through ingestion via the mouth, led to the incorrect assumption that polio could only infect nerve cells (despite evidence to the contrary from both clinical studies and laboratory studies with other polio strains and monkey species).   These mistakes were unfortunate, though understandable given the fact that virology as a science was in its infancy.

However, these failed attempts do not cancel out the fact that animal research, and research using monkeys in particular, was absolutely crucial to the development of vaccines for polio.  Without it the polio vaccine would certainly not have been developed by the end of the 1950’s, and we might even still be waiting for it.

These vital contributions made by animal research to the development of polio vaccines were not limited to the work of Albert Sabin, and include:

  • The discovery by Karl Landsteiner and Erwin Popper in 1908 that polio was caused by a virus, a discovery made by inoculating macaque monkeys with an extract of nervous tissue from polio victims that was shown to be free of other infectious agents.
  • The subsequent discovery by Simon Flexner  that blood serum from infected macaque monkeys could protect against polio infection.
  • The discovery by Carl Kling and colleagues in 1911, following an earlier discovery that polio virus could be isolated from the lymph nodes of the small intestine of monkeys, that polio virus was present in the throat and intestinal tissues of people who dies from polio. Soon afterwards they isolated virus from the intestines of patients suffering from acute polio, and importantly from family members who did not display the symptoms of polio, establishing that healthy carriers played an important role in spreading the disease. In these studies the presence of polio was demonstrated by injecting filtered fluid from the patients into monkeys, the only method then available to confirm the presence of polio (Introduction to Epidemiology, fifth edition, by Ray M, Merill, Jones and Bartlett Learning).
  • The discovery in the early 1930’s by the Australian scientists Macfarlane Burnet and Jean Macnamara that antibodies against one strain of polio did not always protect macaque monkeys against infection with another strain.
  • The discovery by John Enders, Thomas Weller and Frederick Robbins that the polio virus could be grown in a number of tissue types, not just nerve tissue as previously assumed, a discovery that required the use of mice and monkeys to prove that the cultured virus was indeed polio and still capable of causing paralysis.
  • The determination in 1949 by David Bodian and colleagues at Johns Hopkins University that there were three major families of polio virus, referred to as types 1, 2, and 3, and that a separate vaccine would be necessary for each to give broad protection against polio.
  • The discovery by David Bodian and colleagues in the late 1940’s and early 1950’s that the polio virus entered the body through the mouth, and then needed to pass into the blood stream before it could infect nervous tissue, and that if you could block the infection in the blood you could prevent the virus from entering nerve tissue and causing paralysis. The work of Enders and Bodian paved the way for the development of vaccines by Salk and Sabin.
  • The evaluation by Jonas Salk and his colleagues at the University of Pittsburgh  of vaccine candidates produced by inactivating the virus with formalin under a range of conditions, until a vaccine was identified that was effective and safe enough for human trials.
  • The evaluation by Albert Sabin of hundreds of polio virus strains in hundreds of monkeys and scores of chimps before identifying attenuated strains that were capable of efficiently entering the body through the digestive system and provoking an adequate immune response to protect against the different pathogenic strains of polio while not causing the disease themselves.

It is hardly surprising that those close to Albert Sabin are disgusted with the way in which his views are misrepresented by animal rights activists. Writing for the Wall Street Journal two years after his death Albert Sabin’s widow, Heloisa Sabin, discussed the value of animals to his research.

ANIMAL RESEARCH SAVES HUMAN LIVES

The Wall Street Journal, October 18, 1995

by Heloisa Sabin

Mrs. Sabin is honorary director of Americans for Medical Progress.

That scene in “Forrest Gump,” in which young Forrest runs from his schoolmate tormentors so fast that his leg braces fly apart and his strong legs carry him to safety may be the only image of the polio epidemic of the 1950s etched in the minds of those too young to remember the actual devastation the disease caused. Hollywood created a scene of triumph far removed from the reality of the disease.

Some who have benefited directly from polio research, including the work of my late husband, Albert Sabin, think winning the real war against polio was just as simple. They have embraced a movement that denounces the very process that enables them to look forward to continued good health and promising futures. This “animal rights” ideology — espoused by groups such as People for the Ethical Treatment of Animals, the Humane Society of the U.S. and the Fund for Animals — rejects the use of laboratory animals in medical research and denies the role such research played in the victory over polio.

The leaders of this movement seem to have forgotten that year after year in the early ’50s, the very words “infantile paralysis” and “poliomyelitis” struck great fear among young parents that the disease would snatch their children as they slept. Each summer public beaches, playgrounds and movie theaters were places to be avoided. Polio epidemics condemned millions of children and young adults to lives in which debilitated lungs could no longer breathe on their own and young limbs were left forever wilted and frail. The disease drafted tiny armies of children on crutches and in wheelchairs who were unable to walk, run or jump. In the U.S., polio struck down nearly 58,000 children in 1952 alone.

Unlike the braces on Forrest Gump’s legs, real ones would be replaced only as the children’s misshapened legs grew. Other children and young adults were entombed in iron lungs. The only view of the world these patients had was through mirrors over their heads. These, however, are no longer part of our collective cultural memory.

Albert was on the front line of polio research. In 1961, thirty years after he began studying polio, his oral vaccine was introduced in the U.S. and distributed widely. In the nearly 40 years since, polio has been eradicated in the Western hemisphere, the World Health Organization reports, adding that with a full-scale effort, polio could be eliminated from the rest of the world by the year 2000.

Without animal research, polio would still be claiming thousands of lives each year. “There could have been no oral polio vaccine without the use of innumerable animals, a very large number of animals,” Albert told a reporter shortly before his death in 1993. Animals are still needed to test every new batch of vaccine that is produced for today’s children.

Animal activists claim that vaccines really didn’t end the epidemics — that, with improvements in social hygiene, polio was dying out anyway, before the vaccines were developed. This is untrue. In fact, advanced sanitation was responsible in part for the dramatic rise in the number of paralytic polio cases in the ’50s. Improvements in sanitation practices reduced the rate of infection, so that the average age of those infected by the polio virus went up. Older children and young adults were more likely than infants to develop paralysis from their exposure to the polio virus.

Every child who has tasted the sweet sugar cube or received the drops containing the Sabin Vaccine over the past four decades knows polio only as a word, or an obscure reference in a popular film. Thank heavens it’s not part of their reality.

These polio-free generations have grown up to be doctors, teachers, business leaders, government officials, and parents. They have their own concerns and struggles. Cancer, heart disease, strokes and AIDS are far more lethal realities to them now than polio. Yet, those who support an “animal rights” agenda that would cripple research and halt medical science in its tracks are slamming the door on the possibilities of new treatments and cures.

My husband was a kind man, but he was impatient with those who refused to acknowledge reality or to seek reasoned answers to the questions of life.

The pioneers of polio research included not only the scientists but also the laboratory animals that played a critical role in bringing about the end of polio and a host of other diseases for which we now have vaccines and cures. Animals will continue to be as vital as the scientists who study them in the battle to eliminate pain, suffering and disease from our lives.

That is the reality of medical progress.”

 

Animal rights activists are free to express their opposition to the use of animals in research, but they cannot do so by blatantly robbing society of scientific achievements.  This one fact is clear — if our critics had their way, today millions of children would be dead or disabled from polio and other infectious diseases.

* Of course Jonas Salk is equally, if not more, deserving of this accolade.

George is OK: Thank the men who stare down microscopes!

The news that actor George Clooney contracted malaria on a recent visit to Sudan focuses fresh attention on the biomedical research that is being done to defeat the disease.

Anopheles funestus, a mosquito which spreads malaria in the Sudan. CDC Public health Image Library

Clooney said that he is “completely over the disease,”  and added  that his second bout with the illness “illustrates how with proper medication, the most lethal condition in Africa can be reduced to a bad 10 days instead of a death sentence.”

 

While the news reports don’t state which drugs Cloony took to beat malaria, It is most likely that he was treated with artemisinin-based combination therapies (ACTs), which became available in the late 1990s and are now in widespread use.  If that is the case, he has benefited from mouse studies done in China the late 1960s and early 1970s when over 100 traditional herbal remedies were screened in a rodent model of malaria for anti-malarial activity (1). Eventually “Project 523” scored a hit when Professor Tu Youyou identified an extract of the plant qinghao, scientific name Artemisia annua, which had good anti-malarial activity, leading to the development of the artemisinin-based anti-malarials which have become the first-line treatment for malaria in the past decade.

Due to the real risk that malaria will evolve resistance to artemisinin – evidence of this have already been observed – the World Health Organization guidelines for the treatment of malaria stress that artemisinins must always be used alongside other anti-malarial drugs in artemisin-based combination therapy (ACT).  Of course the medical community isn’t just going to rely on combination therapies to slow the development of drug resistance in malaria, efforts are underway to develop new antimalarial drugs, such as the drug Arterolane which recently performed well in phase II clinical trials and whose preclinical development relied heavily on assessment in rodent models of malaria.

Nevertheless, the statistics on malaria are horrendous.  Roughly half of the world’s population is at risk for the disease.   Annually, there are an estimated 350 to 500 million cases, and every year one million people die of malaria every year – and 85% of those are children under the age of 5.

Despite the success of ACTs in combating malaria and dramatically reducing the number of deaths in many countries, sustained research is needed to develop new medicines to replace those that are losing effectiveness due to growing resistance in malaria’s parasite hosts. 

Additionally, scientists are working to develop a vaccine.  Two years ago, Speaking of Research took a look at one effective vaccine candidate, RTS,S , which is now in Phase III clinical trials.  RTS,S, a first-generation vaccine with 30- 50% protection in infants and children lasting about one year, is currently planned for release in 2015. Writing about RTS,S in 2009 Paul wrote about the important role basic and applied animal research played in its development:

The clinical development of RTS,S has been a long process that began as a collaboration between the Walter Reed Army Institute of Research (WRAIR)and GlaxoSmithKline in the late 1980s. Two key discoveries guiding the development of RTS,S were the finding in mice (3) that in order to immunize against malaria infection it is necessary to stimulate a cell-mediated immune response in addition to an antibody-mediated response, and the simultaneous discovery by scientists at WRAIR that incorporating a hepatitis B surface antigen into the malaria vaccine construct improved its ability to induce an immune response in mice and rabbits (4). 

Other vaccines are in earlier stages of development and also hold promise.  Some are being combined with RTS,S, which may lead to a highly efficacious vaccine in 8 to 15 years. One of these vaccines that is being developed by Dr. Simon Draper and colleagues at Oxford University was discussed on the Pro-Test blog in 2008 and has the advantage over RTS,S that it induces immunity against all stages of the malaria parasite’s life cycle, not just the liver stage that RTS,S targets. Further refinement of this and other vaccines – a process that, as a review led by vaccine expert Professor Adrian Hill  of the Jenner Institute in Oxford describes,  involved the study of a variety of combinations of viral vectors with malarial genes in rodent models of malaria - has yielded six candidate vaccines that are now being assessed for safety and anti-malarial activity in early clinical trials in humans.

Speaking of Research celebrates George Clooney’s rapid recovery, even as we advocate for the ongoing animal research that will lead to millions of lives being saved through the treatment, control, prevention and eventual eradication of malaria from the planet.

1)       Liwang Cui and Xin-Zhuan Su “Discovery, mechanisms of action and combination therapy of artemisin” Expert Rev Anti Infect Ther. 2009 October ; 7(8): 999–1013. doi:10.1586/eri.09.68.)

“The biggest achievement of veterinary history”

That was how John Anderson, the head of the United Nations Food and Agriculture Organisation, described yesterday’s announcement by the Global Rinderpest Eradication Programme (GREP) that the dreaded cattle disease Rinderpest has been eradicated.  For over a millennium Rinderpest has stalked cattle herds around the world, often leaving famine in its wake, and in the past century it has had a particularly devastating effect on both domestic cattle and wild animals in Africa.

 

Rinderpest, which once devestated cattle herds around the world, has become the second deadly virus to be eliminated.

 

Eradicating Rinderpest was a huge undertaking, requiring the co-operation of international bodies, national governments, and non-governmental organizations, and on the ground thousands of scientists, veterinarians, and farmers made sure that outbreaks were detected, contained and eradicated. A key part of both the GREP campaign that finally eliminated Rinderpest, and of the national and regional programs that preceded it, is vaccination.

The first attempts to develop a vaccine for Rinderpest took place at the end of the 19th century, including a vaccine derived from the bile of an infected ox by the famous Robert Koch. A more effective vaccine developed by Arnold Theiler and Herbert Watkins-Pitchford which involved simultaneously injecting the animal with blood from an infected animal that contains the virus  (at that time not yet identified) and antiserum from an infected animal that protects the animal for long enough to allow the animals own immune system to respond to the virus.  While these methods were effective they were also risky, a small minority of cattle would often succumb to the disease following vaccination, so these vaccines were usually only used during Rinderpest outbreaks. They did however allow outbreaks to be controlled in a number of countries including India, Egypt and Russia during the first three decades of the 20th century.

An important breakthrough was in the 1920’s when J. T. Edwards of the Imperial Bacteriological Laboratory at Izatnagar (now the Indian Veterinary Research Institute) modified Rinderpest by growing it serially in goats, and after 600 serial passages, and many tests of the virus in cattle along the way, the virus was sufficiently attenuated so that it did not cause the disease but rather conferred lifelong immunity to rinderpest. This live–attenuated vaccine could be freeze-dried for storage and was easier to, but the vaccine still had the drawback that it could cause disease in cattle with a weakened immune system.

The next great advance was in 1962 when Walter Plowright and R.D. Ferris applied the methods used by Albert Sabin to develop the oral Polio vaccine to produce tissue culture rinderpest vaccine (TCRV), a live-attenuated vaccine grown in vitro in calf kidney cells.  To produce the TCRV required many passages of the virus in cell culture, accompanied by frequent and thorough assessment of the virus in cattle. A virus produced by the 90th passage was found to confer immunity while being stable, not spreading between animals, and not causing disease even in cattle with weakened immune systems. Due to its safety the vaccine developed by Plowright could be used to immunize cattle even when there was no immediate threat from Rinderpest, and it vaccines developed from Plowright’s vaccine were key to the final push to eliminate Rinderpest. Walter Plowright did not confine his work to the laboratory, he also worked to improve production of the vaccine and its use in the field, including a program to immunize wildebeest (an important wild reservoir for the virus); small wonder that he was awarded the World Food Prize in 1999.

 

Walter Plowright, who developed the tissue culture rinderpest vaccine. Image courtesy of the World Veterinary Association.

 

The eradication of Rinderpest is a timely reminder that while we may often focus on the contribution animal research makes to human medicine, we should also remember that it is also key to many advances in veterinary medicine.

 

Addendum: Veterinary blogger The Dog Zombie notes that the eradication of Rinderpest, which involved decades of interplay between human medical research and veterinary research, is a good illustration of One Health in action.

 

Paul Browne

Reference:  “Rinderpest and Peste des Petits Ruminants: Virus Plagues of Large and Small Ruminants” Edited by: Thomas Barrett, Paul-Pierre Pastoret and William P. Taylor, Academic Press Inc. (2005) ISBN: 978-0-12-088385-1

Shots without jabs: The future of vaccination.

Vaccines make a crucial contribution to public health, saving hundreds of millions of people from deadly or debilitating diseases every year, but it’s also fair to say that getting your shots is not the most pleasant of experiences. It’s not just a question of short term discomfort, many people suffer from needle phobias that can prevent them from getting necessary vaccination, and wherever you have used used hypodermic needles there is always the question of safe disposal of this biohazardous waste and the risk of needle stick injury. Now research conducted on mice and pigs at Emory University and the Georgia Institute of Technology shows that there may be a safer and less painful way to administer vaccines (1).

Dissolving polymer microneedle patch for vaccine delivery. Image Courtesy of the Georgia Institute of Technology.

The new vaccine patch uses an array of one hundred tiny needles to deliver the vaccine painlessly into the skin, but the clever part is that having done so the needles, which are made from a polymer material known to be safe for clinical use, dissolve within a few minutes so there is no hazardous sharps waste to be disposed of.  This is a significant advantage over previous microneedle patches that used metal or silicon needles. The vaccine is also injected in a solid form which makes it stable and less likely to break down in storage, an important consideration for clinics in developing nations and remote areas of the world.

So how do they know it works? Well they first had to make sure that the needles could deliver the vaccine into skin without breaking, and then quickly dissolve. The team led by Sean Sullivan assessed this using skin obtained from freshly slaughtered pigs, because pig skin is very similar to human skin in thickness and structure, and found that the microneedles delivered the vaccine successfully and then quickly dissolved.

Microneedles immediately after application of the patch to pig skin. Image courtesy of Georgia Institute of Technology.

Of course delivering a vaccine into the skin is not enough, you have to know if that vaccine will stimulate the desired response from the immune system. The team needed to assess whether the vaccine patch could provoke an immune response that is strong enough to protect against subsequent infection, and this is something that can only be properly done in a living animal.  When the vaccine patch was used to immunize mice with an influenza virus vaccine it provoked a robust and sustained response from the immune system, one that was in fact better than that observed with traditional intramuscular injection. Furthermore the vaccine patch immunized mice survived when infected with influenza virus three months after immunization, whereas all non-immunized control mice died.

Microneedles dissolving one minute after application of patch to pig skin. Image courtesy of Georgia Institute of Technology.

Vaccine patches promise a safe, painless and cheap alternative to vaccination via hypodermic needle, and as someone who likes to keep their shots up to date I’m hoping that this new method will succeed in human trials and soon be available in the clinic.

Paul Browne

1)      Sullivan S.P. et al. “Dissolving polymer microneedle patches for influenza vaccination”  Nature Medicine, Published Online 18 July 2010 DOI:10.1038/nm.2182