Yet Another Cancer Vaccine Disappoints
GSK’s much heralded MAGE-A3 cancer vaccine for melanoma and non-small cell lung cancer (NSCLC) reached a Phase III finish line this past week, in this case for melanoma in a trial composed of over 1300 patients. The results were covered in the press (for example, see here and here) and, at first blush, the results were disappointing. While there were no safety issues that arose, melanoma patients treated with the therapeutic vaccine failed to extend disease-free survival significantly when compared with placebo. The GSK vaccine employs MAGE-A3, a cancer-associated antigen found on the tumors of approximately 65% of melanoma patients. A co-primary endpoint for the study was to increase disease-free survival in the melanoma sub-population that is MAGE-A3 positive. The results for this sub-population will not be ready until 2015 and, in the meantime, hope remains for therapeutic utility in this group. GSK is also continuing Phase III trials in NSCLC.
The concept behind the approach is, of course, to educate and activate the immune system to attack cells expressing the tumor-associated antigen. Cytolytic T-cells (CD8+ T-cells) are a crucial immune respondent to therapeutic vaccination. However, a study published earlier this year in Nature Medicine suggested that a common problem underlying therapeutic vaccine efforts to date was the use of short peptide immunogens with lipophilic adjuvants. This combination leads to long antigen persistence and recruitment/sequestration of antigen-directed T-cells at the site of vaccination. The sequestration of antigen-directed T-cells (a T-cell trap) is so extensive that few if any T-cells attack the antigen-bearing tumor cells. [For the paper and an accompanying News and Views, see here and here). Interestingly, induction of T-cell traps doesn’t appear to occur if longer length antigen peptides (n>20) are employed. The possible reasons for this are discussed in detail in the original article and accompanying News and Views, and the reader is referred to them. However, this observation suggested a possible remedy for the poor clinical performance (especially in Phase III) that seemed to plague the field.
Indeed, it appears that the MAGE-A3 antigen employed by GSK is over 100 amino acids in length and is presented as a chimeric protein fused to protein D of Haemophilus influenza. Previously, GSK has presented data at ASCO highlighting the potential of its investigational MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) (see here). According to their press release, “GSK’s ASCIs represent a novel class of medicines designed to train the immune system to recognize and eliminate cancer cells in a highly specific manner. These novel cancer immunotherapeutics combine tumor antigens, delivered as purified recombinant proteins, and GSK’s proprietary Adjuvant Systems which are specific combinations of immunostimulating compounds selected to increase the anti-tumor immune response.” In the present DERMA trial, a randomized, blinded, and placebo-controlled study, a QS-21 Stimulon adjuvant (Agenus) is employed as a component of GSK's novel adjuvant system AS15. Whatever the eventual conclusions deduced from the data concerning why a co-primary endpoint was missed in the DERMA trial, it is now apparent that simply using longer peptide antigens is insufficient to break the trend of disappointing clinical trials for therapeutic cancer vaccines.
As noted above, phase III trial data for MAGE-A3 in NSCLC is expected in early 2014 and there is still hope for the MAGE-A3 vaccine in a subset of the melanoma patient population. Arguably, however, the development of multivalent melanoma-associated antigen vaccines holds greater promise (see, for example, here). These and other efforts will continue unabated as the incidence of melanoma continues to afflict over 76,000 new patients this year in the U.S. alone.
The Upcoming Crop of Vaccines
A report out last week from the Pharmaceutical Research and Manufacturers of America tabulated a total of 271 vaccines currently in development. Of the 271 all are in clinical trials or are under regulatory review. The vast majority, 137, are targeted at infectious diseases with cancer coming in a close second at 99.
Mumps Outbreak in Wales: Waning MMR Protection?
The trivalent MMR vaccine is a stalwart of modern health case, conveying lifelong immunity from measles, mumps, and rubella, especially if the patient receives both of the recommended jabs. A recent article on FierceVaccines by Nick Paul Taylor, citing a report appearing in The Guardian, describes a growing body of data suggesting that while the vaccine works well for measles and rubella, mumps may be another matter.
In the first quarter of 2013, the U.K.’s National Health Service reported 948 cases of mumps versus 673 measles cases, numbers that prompted a national effort to increase the uptake of the vaccine. But half of the reported mumps cases were in individuals who had received at least one jab with MMR. As a result, Public Health England reports that "…some waning immunity may be contributing to transmission." The idea that the protective effects of the vaccine may abate over time is not new for mumps (see, for example, here and here). Exacerbating matters are possible antigenic differences between the vaccine strain and outbreak strains that crop up from time to time (ref1). Moreover, the recent resurgence of mumps in the U.S. and Canada sometimes occurred in the context of high 2-dose vaccination coverage and thus raised the question of the vaccines durable response (ref2).
Vaccination rates with MMR have been under steady pressure over the past decades due, in part, to the now fully discredited theory linking autism and other disorders to the vaccine. Falling vaccination rates are a concern since, if vaccination uptake in the population is not sufficient to maintain herd immunity, vaccination becomes the only means to protect a given individual. And for children who have received only a single round of vaccine, this can be problematic (see this report).
Mumps is a highly contagious, self-limiting viral disease spread through contact with respiratory droplets from an infected person or by sharing food or drink. Prior to introduction in 1967 of the vaccine, mumps was the leading cause of viral meningoencephalitis in the United States, though the actual rate of encephalitis was rare (<2 per 100,000). Typically mumps presents with swollen glands, fever, vomiting, and headache. The disease is typically not severe in children, but older individuals can experience painful orchitis or oophoritis and are at risk for long-term fertility complications.
Thus, mumps joins other vaccine-preventable diseases, such as pertussis (ref3; ref4), TB (ref5), and polio (ref6) that have displayed characteristics of waning long-term protection. As noted in The Guardian article, solving the problem of waning protection can be a knotty one, not easily solved. And in the end, these observations point to limitations in our understanding of long-term T- and B-cell immune memory.
Candidate Dengue Vaccine Shows Promise in Phase 1 Study
A press release out today from the NIH has announced the a candidate dengue vaccine developed by scientists at the NIH has been found to be safe and generate a strong immune response in recipients participating in a phase 1 clinical trial sponsored by the NIAID. The results of the trial have just been published online in the Journal of Infectious Diseases.
The WHO estimates that 50 to 100 million cases of dengue occur worldwide every year with a resulting 500,000 hospitalizations of patients with more severe forms of the disease, most of them children. One third of the world’s population is chronically at risk each year for this viral infection and there are currently neither therapies nor vaccines for this disease.
Dengue fever can because by any of four related viruses, and the NIH’s vaccine candidate, Tetra-Vax DV, is composed of a live attenuated form of each virus. In the Phase I trial, a randomized, placebo-controlled study, the safety and immunogenicity of four different admixtures of a live attenuated tetravalent vaccine were evaluated in 113 naïve adults. Participants were randomized into four groups of 28. Within each group, 20 individuals received a single s.q. injection of one of the tetravalent candidate vaccine combinations, and eight others received placebo.
As described in the press release, "The researchers found that all four candidate vaccine combinations induced antibody responses against each of the dengue viruses. However, one vaccine combination, TV003, appeared to induce the most balanced antibody response against the dengue viruses. A single dose of TV003 resulted in an antibody response to all four dengue viruses in 45 percent of participants and against three of the four viruses in an additional 45 percent. Overall, an immune response to at least three viruses was seen in 90 percent of vaccinees given TV003.
All of the candidate LATV vaccines were also found to be safe: no participants experienced fever or dengue-like illness after vaccination, though 64% of recipients did develop a faint rash at the site of injection.
As also noted in the NIH press release, "...TV003’s inexpensive production cost—less than $1 per dose—is critical to its potential use in developing countries, noted Dr. Whitehead. Manufacturers in Brazil, India and Vietnam—countries where dengue is prevalent – have licensed the vaccine technology for production and further evaluation. Phase II trials to evaluate the safety of TV003 and its capacity to create an immune response will begin soon in Brazil and Thailand."
This news comes on the heels of disappointing clinical results for a more advanced dengue candidate vaccine last fall and provides additional hope for an eventual effective vaccine.
Killed Virus HIV Vaccine Shows Promise in Clinic
The only HIV vaccine under development in Canada shows early signs of promise, according to a report in Fierce Vaccines. The candidate vaccine, dubbed SAV001-H, was developed by Dr. Chil-Yong Kang, professor of virology at the Schulich School of Medicine & Dentistry at Western University in Ontario.
"In the Phase I study, HIV-positive men and women aged 18 to 50 were split into two groups, with 18 people receiving the vaccine and 6 getting a placebo." Among those individuals receiving the vaccine candidate, "... the level of (HIV-1) antibodies increased significantly." In one individual, a 32-fold increase in the blood levels of anti-HIV antibodies was observed.
The vaccine candidate is scheduled to move into Phase II trials next year.
The conceptual approach of using a killed virus vaccine for HIV is not without concern, especially around issues of the extent of virus killed in manufactured preparations. Even low levels of live HIV viirus would expose vaccine recipients to potential disease.
Prevnar-7’s Progressive Impact
A recent paper, published in The New England Journal of Medicine, quantifies the dramatic impact of Prevnar-7, the vaccine against Streptococcus pneumoniae, and seeks to assess whether initial successes were sustained over the past decade.
The question is important since a potential concern is that, with Prevnar’s success, the door would open for other non-vaccine strains of S. pneumoniae (“serotype replacement”) or even other bacterial species to “take over the territory” and cause disease that would blunt the beneficial impact of vaccine. In other words, what bacteria will wind up colonizing our nasopharyngeal passages if not the seven S. pneumoniae strains covered by the vaccine?
As stated in the paper, “The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) into the U.S. infant immunization schedule in 2000 resulted in major reductions in the incidence of invasive pneumococcal disease in all age groups.” One remarkable thing about Prevnar-7 is that its protective effects extended outside the age group actively receiving immunizations, an example of “herd immunity”. A study published in 2006 found that vaccination with Prevnar-7 prevented 800,000 hospitalizations for pneumococcal pneumonia in the U.S. alone. The current study extends this analysis through 2009, prior to any impact from the “next generation” pneumococcal vaccine, Prevnar-13. The current study compares hospitalization rates over three time periods: 1997-1999 (before Prevnar-7), 2001-2006 (early Prevnar-7 years, and 2007-2009 (late Prevnar-7 years).
Over this time span, “…there were 17,892,085 hospitalizations for pneumonia, representing 4.1% of all U.S. hospitalizations other than those for childbirth, including 7.2% of hospitalizations among children and 3.9% of hospitalizations among adults.” And, “Annual rates of hospitalization for pneumonia were highest at the extreme ends of the age spectrum in all 3-year periods, with rates for children younger than 2 years of age similar to those for adults 65 to 74 years of age, at approximately 1000 hospitalizations per 100,000 persons. Rates for persons 75 years of age or older were two to five times as high.”
The results shows that continued immunization with Prevnar-7 through 2009 resulted in deeper reductions in the average annual rates of hospitalizations for pneumonia in the U.S. The results were most notable for the age groups at the extremes of the range. Overall, the authors estimate an age-adjusted annual reduction of 54.8 per 100,000 cases, which translates to 168,000 fewer hospitalizations for pneumonia annually. 47,000 of these fewer hospitalization are found in children less than 2 years of age (the group that is actively immunized) while 73,000 fewer hospitalizations occur annually in the 85+ age group (where there is no routine immunization occurring). There was no significant impact in the age-ranges of 5-17 and 18-39 years.
The authors also found that “Seven years after the introduction of PCV7, invasive pneumococcal disease caused by vaccine serotypes was almost eliminated in children younger than 5 years of age and declined by more than 85% in all unvaccinated age groups.” It is important to note that unvaccinated age groups still retain a substantial residual disease burden for invasive pneumococcal disease. It remains to be seen whether the advent of Prevnar-13 leads to additional reductions and in which age groups.
However, serotype replacement remains a real concern. First noted in 2005 by the CDC [ref1], use of surveillance data now clearly show increased circulation of non-vaccine serotypes 1, 3, 6A, 6C, 7 F and 19A in countries with routine vaccination (ref2). And as first noted by the CDC study, some serotypes, such as 19A, are increasingly drug resistant. Replacement serotypes are important considerations because, as noted in ref2, “The direct and indirect costs associated with pneumococcal disease are high, thus herd protection and infections caused by non-vaccine serotypes both have strong effects on the cost effectiveness of pneumococcal vaccination. Recent evaluations highlight the public health significance of indirect benefits, prevention of pneumonia and AOM [acute otitis media] and coverage of non-PCV7 serotypes by higher valency vaccines.”
Novel TB Vaccine Fails to Protect Infants
The only existing vaccine against tuberculosis, BCG [Bacille Calmette-Guérin], was developed 90 some years ago but provides only incomplete protection. As a result, intense R&D efforts have been directed at finding a better vaccine (with greater and more consistent protection) for TB. One such candidate vaccine is MVA85A [modified Vaccinia Ankara virus expressing antigen 85A ], which is intended as a booster for the standard BCG vaccine. With 1.4 millions deaths annually from TB, the stakes couldn’t be higher.
In a report appearing online in The Lancet, investigators from the University of Oxford found that, in a randomized phase 2b clinical trial of over 2500 infants aged 4-6 months, the vaccine candidate was safe but induced only modest cell-mediated immune responses. The immune response observed in infants was much lower than it previously observed in adults, notably in antigen-specific Th1 T cells whose frequency was only a tenth that observed in adults. The vaccine candidate was found insufficient to protect against the disease since 13% of recipients became infected with TB as compared to 12% in the control group.
As noted by Allison Bryant in a commentary published in Fierce Vaccines, the lack of apparent efficacy for MVA85A is almost beside the point. More than a dozen TB vaccine candidates are currently lined up for testing in humans and this candidate vaccine trial is important, if for no other reason, as simply an important milestone forward in TB vaccine efforts.
Moreover, as reported by Michael Smith in MedPage Today, covering an accompanying editorial in The Lancet, “…the results may not be "a terminal prognosis" for MVA85A or other BCG-boosting candidates now under development, argued Christopher Dye, DPhil, of the World Health Organization, and Paul Fine, VMD, PhD, of the London School of Hygiene and Tropical Medicine. The study raises several questions that have yet to be answered, they wrote, including whether MVA85A could be effective in infants if used independently of BCG, if it might work better as a BCG booster in adolescents and adults, and whether it might work if given to people infected with HIV.”
For Flu, a New Kind of Vaccine
German company CureVac, in a joint research effort with scientists from the Friedrich-Loeffler-Institute, is reporting in the journal Nature Biotechnology, that they have created a new type of influenza vaccine. There are already many different types of vaccines (live, attenuated vaccines; inactivated vaccines; subunit vaccines; toxoid vaccines; conjugate vaccines; DNA vaccines; and recombinant vector vaccines; see this web page for more info) but no one has ever made a vaccine against an infectious agent from messenger RNA [mRNA]. mRNA is the cellular material which conveys information from expressed genes and transports it out of the nucleus to ribosomes in the cytosol for the biosynthesis of new proteins.
In their report, the investigators demonstrate that “…an mRNA vaccine platform that combines the simplicity, safety and focused immune response of subunit vaccines with the immunogenicity of live viral vaccines. Our findings open attractive perspectives for immunization against a broad range of pathogens.” The mRNA vaccine construct encoded the H1N1 viral hemagglutinin, though specially modified to prevent rapid degradation from ubiquitous RNases (after modification, the stability of the mRNA construct was 10,000-fold higher than unmodified mRNA. After dermal injection of mice, the host cells produced the viral protein and this elicited an immune response sufficient to protect the mice from subsequent lethal infection.
Specifically, the authors “…show that mRNA vaccines induce balanced, long-lived and protective immunity to influenza A virus infections in even very young and very old mice and that the vaccine remains protective upon thermal stress. This vaccine format elicits B and T cell–dependent protection and targets multiple antigens, including the highly conserved viral nucleoprotein, indicating its usefulness as a cross-protective vaccine.”
What is also very striking about these results is that the approach obviates the need to grow virus or produce some component of the virus to employ as an immunogen. In principle, one only needs the sequence of the hemagglutinin (or other viral immunogen) and a supply of vaccine could be produced in only six weeks or so, not the six months that it took for the pH1N1 vaccine in 2009, in what was then a highly expedited and herculean effort.
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