All failed attempts to produce a viable vaccine against amyloid-beta in Alzheimer’s disease have one thing in common — they all used vaccine adjuvants that elicit the wrong kind of immune response, says Qantu Therapeutics’ president and CSO, Dante J. Marciani, in a sweeping retrospective analysis that covers errors in past and current development efforts and recommends ways of correcting them.
According to the analysis, “A retrospective analysis of the Alzheimer’s disease vaccine progress – The critical need for new development strategies,“ vaccine development in Alzheimer’s started off on the wrong foot. The Phase 2 clinical trial of the first vaccine, called AN1792, was abruptly terminated when it became clear that the drug triggered the development of meningoencephalitis — a life-threatening inflammation of the brain and the membranes surrounding it.
The vaccine used a molecule called QS-21 as an adjuvant. Vaccine adjuvants are compounds boosting the immune response to an antigen — the structure a vaccine is targeting. At times, the adjuvant is absolutely crucial for eliciting an immune response against an antigen.
Most adjuvants trigger an immune response that is a mix of reactions by immune cells called Th1 and Th2. To simplify, one can say that Th1 reactions are pro-inflammatory while Th2 promotes an anti-inflammatory response with the production of protective antibodies. According to Dr. Marciani, the failure of the first vaccine was that the adjuvant QS-21 elicited a strong Th1, or pro-inflammatory response, that was absolutely devastating in the brain. And, as Dr. Marciani presents his case, all vaccine-development attempts since have failed to take into account the numerous complex facets of the immune system or knowledge about the amyloid-beta protein.
Other scientists did not see it that way, and vaccine development continued with the same types of adjuvants. Adverse events were attributed to a part of the amyloid-beta molecule used in the vaccine, which could activate T-cells to launch a damaging inflammatory response. This region would not be problematic, however, if the vaccine had been combined with an adjuvant triggering only anti-inflammatory Th2 responses, Dr. Marciani says in his analysis, published in the Journal of Neurochemistry.
Nevertheless, all subsequent attempts to produce a vaccine against amyloid-beta have focused on shortened versions of the amyloid-beta molecule, lacking the T-cell triggering part that makes up two-thirds of its length, and destroying its ability to fold into a naturally occurring three-dimensional structure.
Preclinical studies have suggested that natural antibodies against oligomeric amyloid-beta — aggregates of two-to-three protein molecules — exist in the blood of young healthy individuals. Their levels decrease with age, suggesting that humans have a natural immunity against Alzheimer’s disease. But immune processes slow down as people age, allowing the oligomers to exert the neurotoxic actions observed in numerous studies.
These antibodies target what is called a conformational epitope, a part of the amyloid-beta protein that is only present when the protein is folded into its three-dimensional structure. This would prevent the success of shortened fragments of amyloid-beta that are linear, as the immune response would not find such structures to target.
Proof-of-concept can be found, according to Dr. Marciani, in the recent success of aducanumab — a monoclonal antibody that mimicks the conformational epitope. Aducanumab immunotherapy is currently in Phase 3 clinical trials, with previous trials showing rather optimistic results.
Some vaccine development attempts have engineered 3-D versions of the shortened peptide, resembling the conformational epitope. Such constructs need to be linked to a carrier molecule to trigger an immune response, and that is a problem in itself. Numerous studies show that a carrier might elicit an immune response that competes with the immune response against the target peptide, in this case, the fragment of amyloid-beta. This would suppress the intended immune activation in a process known as carrier-induced epitope-specific suppression. Moreover, agents used to cross-link the carrier to the peptide can cause the same kind of suppression. And to make things even worse, the strength of the carrier-induced suppression is dependent on the genotype of the individual — a scenario that is better avoided in clinical settings.
Nevertheless, vaccine development has continued to focus on the shortened amyloid-beta fragment, where almost all attempts involve vaccines against the starting segment of the peptide. Vaccines against this part of the peptide recognize monomeric amyloid-beta, which, according to Dr. Marciani, is an endeavor likely to be completely in vain, since the natural antibodies observed in healthy individuals target the oligomeric form. In his view, mimicking that natural immunity should be the goal of all vaccine development attempts.
In addition, some efforts have also continued with the very same adjuvant used in the AN1792 vaccine or, in many other cases, with adjuvants with a similar pro- and anti-inflammatory mix.
A recent report of two Phase 2 studies of such a vaccine, vanutide cridificar, reported adverse effects in most participants. Any beneficial effects of the vaccine have not yet been reported. Several other versions of similar vaccines are also in clinical trials — some of which have been discontinued.
Another drawback for vaccines targeting monomeric amyloid-beta forms was presented in a recent study, stating that antibodies targeting the starting region of the peptide promote a tendency of amyloid-beta aggregates in the form of fibrils to dissolve into the toxic oligomers, which could worsen disease instead of protecting against it.
Another report, corroborating a damaging effect of vaccines using the starting part of the peptide, showed that such an antibody triggered the faulty processing of the amyloid precursor protein, driving up the production of amyloid-beta.
So, what are the viable options, according to Quantu’s CSO?
He suggests a number of options. A vaccine targeting the other end of the amyloid-beta chain, Abvac40, shows potential to prevent the oligomerization of the protein, and is now in clinical trials. Also, a return to use of full-length amyloid-beta oligomers as a starting point would be advisable. Such constructs unconditionally need to be qualified in a different way than using transgenic mouse models, which he considers a source of much error in Alzheimer’s vaccine development.
Mouse models based on mutations increasing the production of amyloid-beta capture disease mechanisms in only about 5 percent of all Alzheimer’s cases. While they are a needed complement to Alzheimer’s research, overreliance on their validity has led to the numerous drawbacks in vaccine development that moved into clinical trials following positive results in transgenic mice — just to fail in humans.
Instead, new vaccines should be qualified using monoclonal antibodies and highly characterized preparations of intravenous antibodies from healthy donors, in combination with biophysical methods. Such a vaccine would, without question, need to be combined with an adjuvant solely provoking a Th2 anti-inflammatory response, Dr. Marciani said.
Such adjuvants are, however, scarce. One known Th2-specific adjuvant is alum, which unfortunately is a poor adjuvant because it does not elicit a strong enough response in elderly people with weakened immune systems. Qantu’s lead product is attempting to fill this unmet need. QT-0101 is an adjuvant developed to elicit a sole anti-inflammatory Th2 immune reaction, regardless of the immunogens’s nature.
Other options worth exploring are DNA vaccines that do not seem to induce a mixed Th1/Th2 response against amyloid-beta. While such vaccines have been found to induce the production of antibodies against the conformational epitope, the antibody production is low and, again, an aspect that could be overcome with Th2 specific adjuvants.
But the most sensible vaccine approach would be one aiming to prevent the disease rather than reverse it, Dr. Marciani said. According to a report by the Alzheimer’s Association, a treatment that in 2025 would delay the onset of Alzheimer’s by five years would reduce the number of affected individuals in the U.S. by 2.4 million, and produce a savings in healthcare costs worth $83 billion.
A preventive vaccine would be the most cost-effective means to reduce the disease burden, and allow treatments in the form of expensive immunotherapy to be reserved for those already ill.