Researchers at the University of Georgia Cancer Center (GA, USA), led by Geert-Jan Boons, have created a fully synthetic cancer vaccine from a tumor-associated glycopeptide, a Toll-like receptor-2 agonist and a promiscuous peptide T-helper epitope.
Cancer cells often overexpress various sugar components, which have been the targets of many cancer vaccine candidates. However, these cancer-associated carbohydrates are not immunogenic and the fusion of these carbohydrates to a carrier protein is necessary in classical cancer vaccine design. Despite this strategy, immune responses are often raised against carrier proteins while not being elicited adequately against the carbohydrates themselves.
“We needed to come up with a vaccine that does not give our immune system a chance to go after anything else but the tumor-associated carbohydrate,” said Boons. “In other words, there should be no junk that can induce an immune response to something other than the tumor-associated carbohydrate.”
The new synthetic vaccine has been designed carefully with ‘superior properties (that) … are attributed to the local production of cytokines, upregulation of costimulatory proteins, enhanced uptake by macrophages and dendritic cells and avoidance of epitope suppression,’ wrote the authors in their article published in Nature Chemical Biology.
“When we tested our best vaccine, we got really, really fabulous antibody levels that have never been seen before. The levels of IgG antibody production were 100-times better than with conventional approaches,” said Boons. “We have shown that the antibody responses are functional – that is, they can kill cancer cells.”
Having shown that the vaccine could elicit a strong antibody response in healthy mice, which could kill cultured cancer cells, the researchers are now investigating the efficacy of this vaccine in triggering an immune attack against tumors in mice with cancer. If this is successful, a Phase I clinical trial in humans may be initiated soon. However, “there is a very big step going from mice to humans,” cautioned Boons. “Other cancer vaccines have worked in mice but not in humans.”
Sources: Ingale S, Wolfert MA, Gaekwad J, Buskas T, Boons GJ. Robust immune responses elicited by a fully synthetic three-component vaccine. Nat. Chem. Biol. 3(10), 663–667 (2007); University of Georgia, GA, USA: www.uga.edu
Novel approach in HIV vaccine research
Upon infecting the host cell, HIV may have awakened an ancient retrovirus, human endogenous retrovirus (HERV). Targeting cells carrying active HERV may be a novel approach in controlling HIV infection.
HERV is a dormant retrovirus whose genome has become part of the human genome, and our immune system has evolved so that HERV is always kept under control. Researchers from the University of California, San Francisco (CA, USA) and the University of Toronto (ON, Canada) have found that HIV infection could disrupt that control, leading to reactivation of HERV.
“One important limitation to a T-cell vaccine targeting HIV itself is that HIV exists in so many variations and is constantly mutating. If we can find other ways for the immune system to target HIV-infected cells, we can overcome this problem in making a HIV vaccine. HERV may provide us with a good target to test,” said study coauthor Keith Garrison.
The research team found HERV-specific T-cell responses in HIV-positive people that were not present in HIV-negative individuals. These T cells were also different from HIV-specific T cells. Therefore, T-cell vaccines that target and kill HERV-expressing cells can, at the same time, target and kill HIV-infected cells.
“Although these results are preliminary, they encourage new ways to make the immune system potentially target HIV-infected cells,” said study coauthor Mario Ostrowski. The findings were published in the November issue of PLoS Pathogens.
Source: Garrison KE, Jones RB, Meiklejohn DA et al. T cell responses to human endogenous retroviruses in HIV-1 infection. PLoS Pathog. 3(11), e165 (2007).
Chickenpox vaccination may be necessary for UK children
Unlike many countries, such as the USA, Canada, Australia and Finland, chickenpox vaccines are not included in the immunization schedule for children in the UK. A recent article in the November issue of Archives of Disease in Childhood has revealed the rate of chickenpox complications in UK children and suggested that vaccination may be beneficial.
Chickenpox is caused by the varicella–zoster virus, a member of the herpes virus family, which produces an itchy, blistery rash that lasts for approximately a week. The disease is highly contagious yet is mainly unpleasant rather than dangerous; therefore, it is usually treated at home. Severe complications, such as septic shock, pneumonia, encephalitis and even death, may occur in a small number of cases, which require hospitalization. Chickenpox can be prevented easily with currently available varicella vaccines.
According to the current study, the British Pediatric Surveillance Unit received 188 case reports of chickenpox complications in 13 months during 2002–2003. A total of 112 children aged between 0 and 14 years (median age 3 years) met the survey criteria, giving the rate of chickenpox severe complications of 0.82 per 100,000. There were six deaths and 41 cases of sequelae on discharge (mainly ataxia and skin scarring). Hospital stay ranged from 1 to 68 days (median 7 days).
‘Chickenpox has traditionally been viewed as an irritating but inevitable infection to be endured during childhood, a rite of passage during the preschool years. This benign view persists despite evidence that certain groups, including neonates, adults, pregnant women and the immunocompromised, have higher risks of severe disease,’ stated authors of an accompanying editorial.
The chickenpox-related hospitalization rate is between two and five per 1000 infected cases, and the infection rate is increasing in the UK, explained the authors of the original study. ‘The majority of complications, apart from deaths, occur in otherwise healthy children and thus would be preventable only through a universal childhood immunisation programme,’ they commented. Vaccination against chickenpox is the simplest way to address the current situation, concluded the authors.
Sources: Cameron C, Allan G, Johnston F, Finn A, Heath P, Booy R. Severe complications of chickenpox in hospitalised children in the UK and Ireland. Arch. Dis. Child. doi: 10.1136/adc.2007.123232 (2007); Roderick M, Ramanan AV, Finn A. Should the UK introduce varicella vaccine? Arch. Dis. Child. doi: 10.1136/adc.2007.130518 (2007).
Americans may be overvaccinated
Americans are getting booster doses of vaccines that they may not need, a recently published article in the November issue of New England Journal of Medicine revealed.
Immune responses following priming doses of a vaccine are often thought to be short-lived and booster doses are required to maintain a protective level of immune responses in vaccinees. The booster time intervals vary greatly depending on vaccine types, ranging from a few months to several years.
“The goal of this study was to determine how long immunity could be maintained after infection or vaccination. We expected to see long-lived immunity following a viral infection and relatively short-lived immunity after vaccination, especially since this is the reasoning for requiring booster vaccinations. Surprisingly, we found that immunity following vaccination with tetanus and diphtheria was much more long-lived than anyone realized and that antibody responses following viral infections were essentially maintained for life,” explained Mark Slifka, the lead author of the study.
The researchers have analyzed 630 blood samples from 45 volunteers for immune responses against measles, mumps, rubella, chickenpox, mononucleosis, tetanus and diphtheria. Antibodies against viral infections, such as measles, mumps and rubella, were found to remain at protective levels for many decades, even for life. In a previous study published in Nature Medicine in 2003, Slifka and colleagues had already reported unexpectedly long-lived antiviral immune responses following vaccinations. In the current 2007 study, the research team has calculated the half-life of this type of immunity to be 92 years.
“We want to emphasize that proper vaccination is vital for protecting people against infectious disease. We also need to mention that overvaccinating the population poses no health or safety concerns – it may just be unnecessary under certain circumstances. What our study found was that the lifespan of protective immunity for certain vaccines is much longer than previously thought. So what does this mean? Based on this data and other studies, we may want to consider adjusting some of our recommended vaccination schedules. Doing so may reduce the number of required shots that are administered each year in this country while, at the same time, help extend limited healthcare resources,” explained Slifka.
The authors also suggested that people should be revaccinated against tetanus at 30-year intervals instead of every 10 years. “Indeed, other countries, such as Sweden, have changed their vaccination policies and doctors are advised to offer tetanus revaccination only once every 30 years,” said Slifka. “Importantly, this has not resulted in any increase in the number of tetanus cases in Sweden and demonstrates first-hand that switching from the 10-year to 30-year policy is safe and effective. Taking this small step in vaccination scheduling could save hundreds of millions of dollars on healthcare here in the USA.”
Sources: Amanna IJ, Carlson NE, Slifka MK. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007); Hammarlund E, Lewis MW, Hansen SG et al. Duration of antiviral immunity after smallpox vaccination. Nat. Med. 9(9), 1131–1137 (2003); Oregon Health & Science University, OR, USA: www.ohsu.edu
Bacterial communication as a new vaccine target
A new vaccine aimed at a novel target could have important implications for combating resistant ‘super bugs’. “I think the impact of this approach could be really huge, because our approach side steps the resistance problem with common antibiotic treatments”, said Kim Janda, Director of the Worm Institute for Research and Medicine at the Scripps Research Institute (CA, USA).
Increased resistance by staphylococci, in particular the methicillin-resistant Staphylococcus aureus (MRSA), to conventional antibiotics is a major cause of hospital deaths worldwide. The new line of research brings hope as it targets the bacteria’s own communication systems, preventing them from switching to a virulent mode. The advantage of such an intervention is twofold: it would work on already resistant strains; and, since the vaccine is not killing the bacterial cells, the incentive for bacterial resistance would be eliminated.
Bacteria converse by autoinducers, which are molecules emitted as part of a mechanism known as quorum sensing. They are thus able to sense when there are plenty of peers around, indicating a beneficial environment to grow, which in turn prompts a switch to the virulent stage. By sequestering autoinducers, this communication line would be hampered, as would establishment of infection.
With this in mind, the team, whose work was published in the October issue of the journal Chemistry and Biology, designed a so-called ‘hapten’ molecule based on the structure of a known bacterial autoinducer. These haptens have the ability to stimulate the immune system to make antibodies, which can subsequently be used to sequester the original autoinducers.
By injecting the haptens into mice, the researchers managed to isolate such antibodies. In a second round of experiments, these antibodies were then administered into a different set of mice, which had been infected by a resistant S. aureus. As hoped, quorum sensing, as well as infection, was successfully blocked.
In the future, these compounds could be used in conjunction as a passive vaccine to block infections, and as an active vaccine, which, when administered to humans, would induce the production of antibodies to block quorum sensing. Moreover, the researchers explained, if the research proceeds according to plan, one day a 'vaccine cocktail’ might be available to target all resistant strains of bacteria.
Sources: Park J, Jagasia R, Kaufmann GF et al. Infection control by antibody disruption of bacterial quorum sensing signaling. Chem. Biol. 14, 1119–1127 (2007); The Scripps Research Institute, CA, USA: www.scripps.edu