Vaccine development strategies for Alzheimer’s disease should attempt to mirror the natural immunity against toxic amyloid-beta, instead of venturing on uncertain paths, Dr. Dante Marciani argued in a feature article discussing Alzheimer’s disease vaccine development.
The feature, “Rejecting the Alzheimer’s disease vaccine development for the wrong reasons,” which recently appeared in the journal Drug Discovery Today, cautioned about abandoning vaccine development attempts in light of failed trials, since the reason for failure is not a flawed theory, but misguided treatment design.
This is not the first time Marciani — who is the president and CSO at Qantu Therapeutics, with more than 30 years of experience in immunotherapy and vaccine development — attempts to draw attention to what he calls the skewed turns of Alzheimer’s drug development.
He published an extensive retrospective in April highlighting the mistakes he thinks have prevented amyloid research being translated successfully into a treatment. Now, more than six months later, he does not see the change he was hoping for. The wrong targets and methods are still being used, he said, with no lessons learned from clinical trial failures.
Lifting a radically different example, Marciani told Alzheimer’s News Today that it took Zika virus scientists less than nine months to discover that the wrong viral antigen caused an unfavorable immune response.
So what does Marciani believe is the problem with current Alzheimer’s immunotherapy attempts?
Let us first make it clear that Marciani is a strong proponent of the idea that Alzheimer’s disease should be prevented or delayed, rather than treated in patients already on the path of neurodegeneration.
“Since vaccination is cost-effective and easy to administer, it is quite possible that after thorough clinical studies in large populations, an effective AD vaccine may be used in the early middle-aged population to prevent or delay onset of this disease later at a more advanced age,” Marciani told Alzheimer’s News Today.
Studies have indicated that humans have a natural protection against toxic forms of amyloid-beta, and antibodies against amyloid oligomers have been isolated from healthy elderly people. But aging is an enemy of natural immunity, and as people grow older, their natural defenses fail.
But mimicking natural defenses through a treatment could restore lost immunity. As an example, Marciani highlighted the current development of aducanumab — a passive immunization using an antibody isolated from older cognitively healthy humans. Although clinical trials in early Alzheimer’s patients are still ongoing (NCT02484547 and NCT02477800), results have so far been promising.
In terms of active immunizations, all attempts have so far failed, starting with the very first compound, called AN-1792. The drug was a synthetic version of full-length amyloid-beta with an adjuvant called QS-21. Adjuvants are added to vaccines to stimulate the immune system’s response to the target antigen (immunogen), the molecule that will cause an immune reaction. Essentially, the immunogen tells the body to launch an immune response to a target protein (amyloid-beta) and the adjuvant determines the type of response.
A clinical trial of the compound (NCT00021723) was cut short as some patients developed meningoencephalitis, an inflammatory brain condition.
Since then, development has continued failing to take key immunology factors into account, according to Marciani. A successful vaccine needs to be composed of a protein part, acting as the immunogen, and an adjuvant, triggering the desired type of immune response.
It is here that views differ. The majority of scientists blamed the peptide part for the brain inflammation caused by AN-1792, and continued development with shorter fragments of the amyloid peptide.
According to Qantu’s CSO, this was a double mistake. In his view, fault lies with the adjuvant.
“The problem is that it is not possible, like all the developed Alzheimer’s disease vaccines have done, to modulate immunity by modifying the immunogen, since the adjuvant is the one driving the type of immune response,” Marciani told Alzheimer’s News Today.
The type of vaccine adjuvant used in the first, and again in some later trials, triggers an inflammatory reaction that is completely unsuitable for the treatment of elderly patients who already have ongoing brain inflammation, he said.
An immune reaction can be broadly divided into an inflammatory response, guarded by Th1-type immune cells, or an anti-inflammatory response, controlled by Th2-cells. Later trials have all used unsuitable adjuvants, that either triggered inflammation or were unable to elicit a response in elderly people.
Although immune reactions in later trials were not as severe as for AN-1792, studies could not show any benefit for the tested drugs.
The second problem, Marciani pointed out, was the use of shorter amyloid fragments as immunogens. They were chosen as scientists believed that their use would prevent dangerous immune reactions.
But the fragments are unable to direct an immune response to the toxic amyloid-beta oligomers, which need immunogens targeting the so-called conformational epitope of amyloid. Rather, many of them target plaque, which some researchers think may worsen Alzheimer’s by releasing oligomers that were previously bound in the plaque.
The way to go forward, Marciani maintained, is to use amyloid-beta conformational epitopes as immunogens, possibly together with tau immunogens, together with adjuvants that trigger a “good” type of immune response. This Th2-based response would also not interfere with the natural protection against infections, which relies on Th1-mediated mechanisms.
While such adjuvants are not common, they do exist. Qantu has developed a pure Th2 anti-inflammatory vaccine adjuvant, but so far, interest from the Alzheimer’s community is lacking.
Also of possible value for Alzheimer’s vaccine development are findings of certain carbohydrate molecules that help to protect a fetus against an immune response during pregnancy. These molecules become attached to antibodies, which essentially alter their response.
Similar mechanisms may be employed to create the right type of immune reactions in Alzheimer’s patients, particularly as the attachment of these carbohydrates to antibodies can be triggered with an anti-inflammatory type of adjuvant.
Marciani does not believe it is time to abandon the amyloid hypothesis just yet, particularly not in the light of failed trials. Instead, he argues, existing knowledge in immunity and adjuvant mechanisms should be leveraged to develop a vaccine.
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