Tag Archives: vaccine

HPV vaccines and cervical cancer – a success in animals is a success for humans

A recent article in the journal Pediatrics reported that vaccination against human papilloma virus (HPV) resulted in a 64% reduction in infections in girls aged 14-19 (1).

The vaccine, Gardasil, came onto market in June of 2006 and protects again four different HPV types: the two most prevalent high-risk viruses, HPV16 and HPV18, and the two most common causes of benign genital warts, HPV6 and HPV11. Protection against HPV16 and HPV18 is particularly important to human health given that these viruses are responsible for 70% of cervical cancers in women – a cancer which caused 270,000 deaths in 2012. The effectiveness of the HPV vaccine is excellent news in our quest to reduce the deadly toll of cervical cancer, and received widespread coverage in the mainstream media.

Vaccination against HPV prevents cervical cancer. Photo: Art Writ

Vaccination against HPV prevents cervical cancer. Photo: Art Writ

Where did the HPV vaccine come from?

As with most medical discoveries, animal research played a vital role in the development of the HPV vaccine, one that is discussed in depth in a recent issue of FASEB’s “Breakthrough in Bioscience” . From rabbits, to mice, to non-human primates, many species were involved in uncovering the link from HPV-cervical cancer and in developing the first effective vaccine.

Early observiations

In the early 1930s, Richard Shope isolated viral particles from wart-like tumors (papillomas) on the Eastern cottontail rabbit. These particles were then applied to non-infected rabbits, and within six to 12 days these rabbits, too, had developed warts. Shope also observed that the warts of the infected rabbits often progressed to cancer after about four months. This was the first animal model showing the progression from viral infection to cancer.

Papillomaviruses are highly species specific. That is, a rabbit papillomavirus will only replicate in rabbits, and a human papillomavirus will only infect humans. As such, an animal model that would effectively grow human papillomavirus was necessary to begin to understand the virus better. Immunocompromised mice (mice that lack a functional immune system) proved to be an effective model in which to grow human papillomaviruses. This breakthrough provided researchers the means understand the virus’s lifecycle as well as the host’s immune response paving the way towards the development of the HPV vaccine.

 Wild rabbit with tumors caused by papillomavirus infection

Wild rabbit with tumors caused by papillomavirus infection

While much was being learned about the biology of papillomaviruses through  animal studies, the demonstration by Harald zur Hausen and colleagues at the University of Freiburg that HPV was present in the majority of cases of cervical cancer suggested that vaccination may provide a means to prevent this deadly disease.

The path to a vaccine against cervical cancer

It wasn’t until the early 1990s that scientists were able to determine what the components of a vaccine should be. Because HPV is a DNA virus, it would have been unsafe to deliver the DNA since it alone is enough to cause cancer. Researchers needed an alternative, and they found that in the discovery of virus-like particles (VLPs), which are multiple copies of the main structural protein of HPV. Injection of bovine papillomavirus capsid protein L1, a protein that forms the outer shell of the virus, was found to induce a strong immune response in rabbits, and that the rabbits produced antibodies that bound strongly to bovine papillomavirus in vitro.  Researchers now needed to determine if delivering the VLPs were safe and effective protecting against HPV.

Because of the species-specificity of the papilloma viruses, animal efficacy trials had to be done with the animal equivalent of the vaccine. Investigators relied upon the biological effects of nonhuman papillomaviruses in nonhuman models to form the groundwork for HPV studies. The  bovine VLP based vaccine was found to  protect against the virus in cattle, and subsequent species-specific versions of the VLP vaccines were tested in rabbits and dogs. The vaccinated animals produced high levels of antibodies and the vaccines were at least 90 percent effective at preventing warts following exposure to papillomavirus. Next, VLPs of human papillomaviruses were tested in nonhuman primates to see if they could induce an immune response, and they did.

Clinical trials with human volunteers showed that the HPV VLP vaccines induced high levels of antibodies against HPV. Women vaccinated in the trials were also protected from persistent HPV infection and precancerous cervical changes. Because of the success in the human trials, Gardasil, the first vaccine against HPV, was approved by the FDA in 2006. In 2015, FDA approved a new version of the vaccine that is effective against nine types of HPV.

The value of vaccines…the need for animal research

The widespread coverage of the study showing the effectiveness of vaccination against HPV in preventing cervical cancer is a sign of how people appreciate  the importance of vaccination to protect against disease, despite ongoing misinformation campaigns  by misguided – and sometimes sadly high-profile – anti-vaccine activists.

Another sign of the importance people place on vaccines play protecting human health from disease comes from the UK, where a petition to the UK Parliament  asking the Government to “Give the Meningitis B vaccine to ALL children, not just newborn babies” has become the most popular UK Government e-petition to date. The UK was the first country to introduce a vaccination programme – with the Bexsero vaccine –  in babies against Meningitis B, and MPs and the government will need to weigh the benefits of increasing protection against the cost of the vaccine carefully.

Whatever their decision, it is good to note that the public recognize the critical role vaccines play in protecting health. They should also remember the critical role played by animal research in vaccine development, indeed, in an earlier post on this blog we discussed the innovative “reverse immunology” approach in mice that led to the development of Bexsero.

While we rightly celebrate the benefits of vaccination, and advocate for vaccines to be made available to all who need them, we should also remember where those vaccines come from, and ensure that the animal research that is so vital to their development continues.

Anne Deschamps

  1. Lauri E. Markowitz, Gui Liu, Susan Hariri, Martin Steinau, Eileen F. Dunne, Elizabeth R. Unger “Prevalence of HPV After Introduction of the Vaccination Program in the United States” Pediatrics, Published Online 19 February 2016. http://pediatrics.aappublications.org/content/early/2016/02/19/peds.2015-1968

One step closer to a vaccine for cytomegalovirus: Monkeys transmit CMV the same way as humans

Today’s guest post is by Jordana Lenon, Wisconsin National Primate Research Center and Kathy West, California National Primate Research Center.

PregnantWomanResearchers at Duke and Tulane take the lead, the National Primate Research Centers provide critical resources and expertise in this first-ever proof of CMV placental transmission in nonhuman primates.

Researchers now have a powerful new model for working on a vaccine for cytomegalovirus, or CMV, which is the leading infectious cause of birth defects worldwide.

Now, for the first time, a nonhuman primate CMV has been demonstrated to be congenitally transmitted similar to congenital HCMV infection. The discovery was published this week in the high impact journal Proceedings of the National Academy of Sciences and reported in The New York Times and Science Daily, among other news outlets.

Rhesus macaque mothers can transmit CMV across their placentas to their unborn infants, discovered the teams of co-senior study authors Sallie R. Permar, M.D., Ph.D., Duke University, and Amitinder Kaur, M.D., Tulane University. The lead author was Kristy Bialas, a post-doctoral fellow at the Duke Human Vaccine Institute.

Rhesus monkeys at the California National Primate Research Center. Photo credit: Kathy West

Rhesus monkeys at the California National Primate Research Center. Photo credit: Kathy West

The finding establishes the first nonhuman primate research model for CMV transmission via the placenta. The macaque reproductive, developmental, and immunological systems are highly analogous to those of humans. Thus, scientists can now utilize the biologically relevant RhCMV system in a controlled scientific setting to try to find new pathways towards an HCMV vaccine.

“A huge impediment to CMV vaccine development has been our lack of ability to determine what immune responses would be needed to protect against mother-to-fetus transmission,” said Permar, of the Duke Human Vaccine Institute in a Duke Medicine news release Oct. 19.

“It means that we can now use this model to ask questions about protective immunity against congenital CMV and actually study this disease for which a vaccine is urgently needed,” said co-senior author Kaur, of the Tulane National Primate Research Center in a Tulane University release Oct. 19.

The rhesus monkey model for HCMV persistence and pathogenesis has been developed over the past 30 years by co-author Peter Barry, Ph.D., California National Primate Research Center (CNPRC) core scientist, and co-developer of the rhesus intrauterine pathogenesis model with Alice Tarantal, Ph.D., CNPRC core scientist. Barry has recently shown that there is a strong immune response in rhesus monkeys to a potentially paradigm-shifting approach to HCMV vaccine design, and contributed important expertise and resources to this current research.

CNPRCrhesus,K_WestUCD, 4

Rhesus monkeys at the California National Primate Research Center. Photo credit: Kathy West

The work highlights the collaboration of Duke University researchers with experts in rhesus immunology and virology at the National Institutes of Health National Primate Research Centers. Contributing authors also included David O’Connor, Ph.D., and Michael Lauck, Ph.D., experts in macaque virology, pathology and genetics at the Wisconsin National Primate Research Center, Xavier Alvarez, Ph.D., at the Tulane National Primate Research Center, and Takayuki Tanaka, D.V.M., Harvard Medical School and the New England National Primate Research Center, which provided macaques for the study. Additional authors’ contributions are included in the Duke news release.

The research was funded by National Institutes of Health (NIH) Office of the Director, NIH National Cancer Institute, NIH National Institute of Allergy and Infectious Diseases, NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Derfner Children’s Miracle Network Research Grant.


Kristy M. Bialas et al. “Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission” Proc Natl Acad Sci U S A. 2015 Oct 19. http://dx.doi.org/10.1073/pnas.1511526112

Cotton Rats, Calves and Clinical Trials: New RSV vaccine shows great promise.

Respiratory syncytial virus (RSV) affects almost two-thirds of babies in their first year of life, and is a leading cause of bronchiolitis and severe respiratory disease in infants, young children, immunocompromised individuals, and the elderly throughout the world. It is a major cause of hospital admission for infants, and results in up to 200,000 deaths per year in children under the age of 5 years worldwide. Development of an effective vaccine is a public health priority, but has proven difficult, in part due to fact that RSV infection cannot be easily studied in the standard mouse and rat species that are most commonly used in laboratory research.

Oxford University researchers have announced the successful completion of the first trial of a vaccine against RSV in adult humans, which indicated that the vaccine was safe and could induce a robust immune response (though this Phase 1 study did not evaluate its ability to protect against RSV).

In winter RSV accounts for more than 10% of UK infant hospitan admissions.

In winter RSV accounts for more than 10% of UK infant hospital admissions.

In two papers published back-to-back in the journal Science Translational Medicine this week, the University of Oxford team and their colleagues at The Pirbright Institute and the Italian biotechnology firm Okairos (now Reithera Srl) report on the successful Phase 1 clinical trial in adult human volunteers, and the animal studies that led to the trial (1,2).

The basis for their vaccine was a vector derived from the chimpanzee adenovirus PanAd3, which was modified to express several highly conserved human RSV (HRSV) proteins, which they had shown could provide a good level of protection against RSV infection in cotton rats, which are one of the less commonly used laboratory animals, but a very useful model of viral infection of the respiratory system. The cotton rat immune system more closely resembles that of humans at a genetic level than that of more commonly used laboratory mouse and rat species, and because of this similarity cotton rats have been successfully used to evaluate novel therapies for RSV prior to clinical trials, including predicting the efficacy of these drugs in children. As we discussed in an earlier post on the development of gene therapy for Hemophilia B, choosing the right adenoviral vector for the task is critical, and the chimpanzee adenovirus was chosen because there is no preexisting immunity to it in the human population that would compromise its effectiveness as a vaccine vector.

Because studies with other virus-vectored vaccines had shown that heterologous prime/boost with Chimpanzee adenovirus based vector followed several weeks later by a modified vaccinia Ankara (MVA) – a vector used in several experimental vaccines, including HIV vaccines – generates a stronger  immune response than with chimpanzee adenoviral vector alone, the researchers next examined this strategy in cotton rats, demonstrating that intranasal prime/boost immunization was effective in protecting against infection, and did not lead to adverse effects.

The cotton rat - a valuable model for studying lung disease. Image: J.N. Stuart

The cotton rat – a valuable model for studying lung disease. Image: J.N. Stuart

While the cotton rat is a valuable model for the study of respiratory infections, it does not demonstrate all the clinical features of RSV infection, the infection tends to be less severe and to be cleared more quickly in cotton rats than in human infants, and  the extent to which vaccine efficacy in the cotton rat model of HRSV can predict efficacy in humans  is unclear. The scientists therefor evaluated the prime/boost vaccine in a more stringent model, calves, which are the natural hosts of the bovine form of RSV – called bovine RSV (BRSV). The disease course and epidemiology of BRSV infection in calves is very similar to that of HRSV in children, and the very high degree of similarity in sequences of the BRSV proteins to their HRSV equivalents used to develop the vaccine  suggested that the calf would be a valuable preclinical animal model to evaluate the safety and efficacy of their prime/boost vaccine strategies (2).

The results of this evaluation indicated that the different vaccination strategies they assessed were safe and did not cause any adverse immune responses, and showed that heterologous vaccination strategies that used an intranasal administration of the  PanAd3-based vector followed by intramuscular administration of the MVA-vased vector provided superior protection against BRSV infection compared to the PanAd3-based vector alone, or repeated doses of the PanAD3-based vector. As the authors described in the article reporting on the successful phase 1 trial (1) noted in their introduction, these studies paved the way for the evaluation of this vaccine strategy in 42 human volunteers:

In developing this approach toward an RSV vaccine in humans, homologous and heterologous combinations of PanAd3-RSV, including IN vaccination route, and MVA-RSV were tested in preclinical models. The genetic vaccines elicited RSV-specific neutralizing antibodies and T cell immunity in nonhuman primates and protective efficacy in challenge experiments in rodents with human RSV and in young seronegative calves with bovine RSV (32, 33). Of critical importance in both rodent and bovine challenge models was the absence of immunopathology associated with ERD after vaccination, with the calf model acting as a translational model for the development of a vaccine for the pediatric population. All regimens fully protected the lower respiratory tract from bovine RSV infection in the calf, and heterologous combinations resulted in sterilizing immunity in both upper and lower respiratory tracts (33).

The demonstration that the prime/boost vaccine strategy developed by the Oxford University team can safely induce a strong immune response in adult humans, and protect against RSV infection in both the cotton rat and calf models, is very promising, and pave the way for further clinical trials.  Professor Andrew Pollard of the Oxford Vaccine Group, who lead the clinical trial, is keen to now move the development of this much needed vaccine forward:

Both components of the vaccine were found to be safe and to create an immune response.

‘While I am delighted with these results, this was just a first trial. We need this vaccine for children and the elderly and that is where the efforts in vaccine development will now focus.’

Paul Browne

  1. Christopher A. Green et al. “Chimpanzee adenovirus– and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults” Science Translational Medicine, Vol 7, Issue 300, 300ra126, 12 August 2015 Link
  2. Taylor G. et al.”Efficacy of a virus-vectored vaccine against human and bovine respiratory syncytial virus infections” Science Translational Medicine, Vol 7, Issue 300, 300ra127, 12 August 2015 Link

Ebola virus vaccine developed to protect wild gorillas and chimpanzees

The current Ebola virus outbreak in Guinea, Sierra Leone and Liberia is a stark reminder on the need for effective therapies and vaccines for this disease, which has claimed the lives of thousands of people in West Africa in a series of outbreaks since the 1970’s.

It is not just the human inhabitants of West Africa who are threatened by the Ebola virus. Over the past few decades thousands of endangered gorillas and chimpanzees in the wild have been killed in devastating outbreaks, including over 5,000 gorillas in just one outbreak in Northern Congo in 2002—2003.

A new report (1) by scientists at the University of Cambridge and New Iberia Research Center illustrates “high conservation potential” of vaccines for endangered wild primates devastated by viral disease. The paper published today in the prestigious scientific journal PNAS shows that candidate vaccines which despite very promising preclinical results never complete the expensive licensing process for human use – can be co-opted for use in populations of highly endangered species such as gorillas and chimpanzees.

The study was supported by an unusual constellation of organizations, including the Universities of Cambridge and Louisiana, the conservation charity Apes Incorporated, the US Army Medical Research Institute of Infectious Diseases and the biotech company Integrated BioTherapeutics Inc.  The work was conducted at the US’s New Iberia Research Center in Louisiana, one of the research facilities that houses chimpanzees who are not owned by the National Institutes of Health.

This is the first time that a conservation-specific vaccine trial has been undertaken on captive chimpanzees, and proves that a vaccine against Ebola virus is both safe and capable of producing a robust immune response in chimpanzees.

The research team, led by Dr Peter Walsh of the University of Cambridge, administered captive chimpanzees with a new virus-like particle (VLP) vaccine being developed by the biotech company Integrated Biotherapeutics for use on humans. While they did not challenge the vaccinated animals directly with Ebola, researchers tested whether antibodies harvested from the chimpanzees’ blood could protect mice against the deadly virus. They also monitored the chimpanzees in case the vaccine produced health complications.

Results showed that the vaccine is safe in chimpanzees. The vaccinated chimpanzees developed robust immune responses, with virus-specific antibodies detected as early as 2 to 4 weeks after the first vaccination in some animals and within 2 weeks of the second vaccination in all animals.

The antibody transfer study is not the only evidence that this vaccine will work. In 2007 a key paper (2) published in The Journal of Infectious Diseases by Dr Kelly Warfield of the US Army Medical Research Institute of Infectious Diseases – who was also first author on today’s PNAS paper – demonstrated that the VLP vaccine used to vaccinate chimpanzees provides rhesus macaques with very robust protection against the Ebola virus. The 2007 paper also highlights earlier studies in mice and guinea pigs that allowed the refining and evaluation of VLP vaccines against challenge with filoviruses such as Ebola and Marburg, work that underpinned the development of this vaccine.

Transmission electron micrograph of Ebola virus. Courtesy of the Centers for Disease Control and Prevention

Transmission electron micrograph of Ebola virus. Courtesy of the Centers for Disease Control and Prevention

Next steps:  Testing in captive apes prior to field trials

The authors of today’s paper note that these VLP vaccines currently require multiple administrations to reach “full potency”, but could prove the difference between survival and extinction for species that are highly endangered or immunologically fragile but also easy to vaccinate.

Peter Walsh stressed the need to test this vaccine on captive ape populations prior to field trials.

We need to be pragmatic about saving these animals now before they are wiped out forever, and vaccination could be a turning point. But park managers are adamant – and rightly so at this stage – that all vaccines are tested on captive apes before deployment in the wild. This means access to captive chimpanzees for vaccine trials.”

The ability to test new vaccines for conservation purposes relies on research access to captive chimpanzees, but this access is now under threat just as the recognition of its necessity is increasing in the conservation community.

The US Fish and Wildlife Service is now considering regulations that would end all biomedical testing on captive chimpanzees over the next few years – the US being the only developed country to allow such research. The study’s authors believe that the US should establish a “humanely housed” captive chimpanzee population dedicated solely to conservation research.  The US already has research facilities with humane housing, including social groups, complex enclosures, expert behavioral management to provide enrichment, cognitive engagement, excellent clinical care and chimpanzees trained for cooperative clinical procedures. Thus, it is possible that the need for conservation research could be met by existing populations or centers.

Peter Walsh suggests that, by ending captive research in an effort to pay back an “ethical debt” to captive chimpanzees, the US Government is poised to “renege on an even larger debt to wild chimpanzees” at risk from viruses transmitted by tourists and researchers – as safety testing on captive chimpanzees is required before vaccines can be used in the wild.

“There is a large pool of experimental vaccines that show excellent safety and immunity profiles in primate trails but are never licensed for human use, we’ve demonstrated that it’s feasible for very modestly funded ape conservationists to adapt these orphan vaccines into conservation tools, but the ability to trial vaccines on captive chimps is vital. Ours is the first conservation-related vaccine trial on captive chimpanzees – and it may be the last.

“Although Congress specifically instructed the National Institutes of Health (NIH) to consider the conservation value of captive chimpanzee research, no findings on its possible impact were presented (in the 2011 Institute of Medicine report – SR). If the biomedical laboratories that have the facilities and inclination to conduct controlled vaccine trials ‘liquidate’ (by which he means retire to sanctuaries – SR) their chimpanzee populations, there will be nowhere left to do conservation-related trials.”

Consideration of the work, its continuation, and implications for wild chimpanzees poses challenging ethical questions, particularly in light of recent changes in US chimpanzee research.  They are questions worth serious discussion not only to inform the future of the vaccine research and conservation efforts, but also because they highlight some of the core issues in decision-making about nonhuman animal research.  Primary among the philosophical and pragmatic questions is whether it is ethical to subordinate the interests of individual animals to those of the species, or of other species.  Should some captive chimpanzees be subjected to invasive, infectious disease research in order to potentially benefit wild apes—not only chimpanzees, but also the gorillas who are most threatened by Ebola?  Another set of questions surround which chimpanzees should be used in this research.  Should it be chimpanzees housed in research facilities in the US who are now to be retired to sanctuaries?  Chimpanzees privately owned by research facilities in the US?  Zoo chimpanzees in Europe who are not intended to breed?

While none of these questions are new, progress in Ebola vaccine development and testing puts into sharp relief the kinds of serious ethical challenges that should engage both the scientific community and the broad public.  The questions are not, as the quote from Peter Walsh suggests, relevant only in the US, they are—like many issues in conservation—global.  The results of scientific study and medical progress are not limited to the country in which the research is performed and in this case, it is the global community that has interests in protecting highly endangered African ape populations.

Ethical consideration of conservation goals vs individual ape’s interests

Invasive research with chimpanzees is permitted in a number of countries, including both the US and the UK, when the goal of the research is to benefit the species itself.  At the heart of this justification is priority of the interests of the species, rather than the interests of the individual animal. Subordinating the individual ape’s interests to those of his own species is generally consistent with conservation and environmental ethics, where the basic overarching goal is protection of natural resources, balance, and preservation of endangered species.

By contrast, the basic position of those arguing for personhood for great apes, or for animal rights, is to protect the interests of the individual. From the latter perspective, using captive chimpanzees to develop and test a vaccine for a disease that they do not have and that is unlikely to pose a threat to them, would be ethically prohibited.

It is the conservationist position that appears compatible with performing infectious disease and invasive research with captive animals in order to potentially protect highly endangered wild populations from a disease that greatly affects their survival and future.  Whether the species’ interests should outweigh the individual’s as ethical justification for the research and testing is not the only question, however.  We might also ask which individuals should serve in the research?  Should these be laboratory chimpanzees?  Those living in zoos?  Sanctuaries?  The research was conducted in the US, but just as well could be conducted in the UK or other countries with appropriate scientific resources and expertise.

The use of chimpanzees in US biomedical research has received a great deal of attention in the past several years, with the frequent assertion that it is one of only two countries that continue chimpanzee research.  What is actually true is that the US has maintained chimpanzees in research facilities that serve the global scientific community. Foreign scientists, including the British researcher involved in the Ebola vaccine study and Canadian scientists, conduct research in US research centers with chimpanzees.  Following the recent National Institutes of Health decision to move away from the small amount of invasive and infectious disease research involving chimpanzees and retire almost all of its research chimpanzees, it is now far less clear that the US differs substantially from other countries with respect to being the location where Ebola vaccine research should occur.

Given the nature of the justification for the work, there appears to be no legal reason that it would be opposed in the UK or other countries that allow for invasive studies meant to benefit the species. The real threat is that if chimpanzees are not available in research facilities it will be impossible to test vaccines to protect wild apes against deadly diseases, even where regulations permit such research.

So the primary obstacle to performing this work in the UK or elsewhere in the EU might be the absence of laboratory chimpanzees; however, like many countries, the UK does hold captive chimpanzees in other types of facilities. The justification for the work appears to fall within current use of European zoo chimpanzees for research to improve the health of the individual or the species, a recent example being research on heart disease in Zoo ape populations. In addition while the EU Directive on animals in scientific research forbids the use of apes in biomedical research, this ban does not cover “veterinary clinical trials required for the marketing authorisation of a veterinary medicinal product” which would cover vaccines against Ebola or other infectious diseases.

The inherent weighting of species’ interests over the individual’s interests for the Ebola vaccine work is  consistent with the ethical justification often offered for keeping endangered species captive in zoological parks in order to serve conservation goals.  These goals are thought to be served in two ways in zoos: First, by allowing animals to reproduce in carefully managed breeding schemes where decision-making is driven by the goal of maintaining genetic diversity.  In this way, populations of endangered animals are continued within protected environments to guard against the species becoming extinct should the wild population disappear.  The interests of the individual animals may be served by the management practices, but the individual’s welfare is not the primary consideration. Thus, individuals may be removed from stable social groups to move to other zoos and form new breeding pairs, other individuals may not have the opportunity to reproduce.  Surplus males may be castrated, or may live in all-male social groups.  The recent controversy over the killing of a young male giraffe in a Danish zoo provided a vivid example of subordinating an individual animal’s interests to those of the group, species, or zoo.

A second justification offered for zoos is that they provide opportunities for public education that in turn can increase public support for conservation in the wild. The first goal could be served by keeping animals in situations without public display, in sanctuary or private park settings. Thus, it is this second goal that is the primary justification for public zoos. Given that the primary ethical justification for maintaining captive apes in zoos is related to conservation, the idea of considering these animals within the pool of eligible research subjects for vaccine development and testing to serve conservation goals is not unreasonable.

Consideration of the work by Peter Walsh, Kelly Warfield and colleagues, its next steps, and implications for wild chimpanzees poses challenging ethical questions.  The choice to develop and test a vaccine may harm individual animals, but benefit some of their species and other apes, in this case gorillas (and potentially also humans if the threat from Ebola grows). Some will argue that it is wrong to use individual animals in work that does not benefit them directly, though benefit to others has long been considered an adequate justification for clinical trials in humans. Here, ruling out benefits to others as a justification for research would eliminate the possibility of a vaccine that could save highly endangered wild populations.

Questions about which animals serve in research and where the work is undertaken clearly merit serious consideration that takes into account global responsibilities and the recent changes in US chimpanzee research.  Today’s announcement demonstrates that making choices about animal research is complex, with harms not only in action, but also inaction.  The work should stimulate serious, thoughtful discussion not only within the scientific, conservation, and animal protection communities, but also among policy makers and the wider public.

Paul Browne, PhD and Allyson J. Bennett, PhD

  1. Warfield KL, Goetzmann JE, Biggins JE, Kasda MB, Unfer RC, Vu H, Aman MJ, Olinger GG, Walsh PD “Vaccinating captive chimpanzees to save wild chimpanzees” PNAS 2014 Published online 26 May 2014. http://www.pnas.org/cgi/content/short/1316902111
  2. Warfield KL, Swenson DL, Olinger GG, Kalina WV, Aman MJ, Bavari S. “Ebola virus-like particle-based vaccine protects nonhuman primates against lethal Ebola virus challenge.” J Infect Dis. 2007 Nov 15;196 Suppl 2:S430-7. PMID: 17940980

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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.


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