A dual vaccine against influenza & Alzheimer's disease failed to enhance anti-β-amyloid antibody responses in mice with pre-existing virus specific memory
Introduction
Alzheimer's disease (AD) is the most frequent cause of dementia, which is characterized clinically by a progressive cognitive decline eventually resulting in death, usually within 10 years of diagnosis. Although there have been numerous advances in treatment options currently there are no effective treatments that can halt or reverse AD.
The neuropathological features of AD include neurofibrillary tangles (NFT), deposition of Aβ soluble (monomeric, oligomeric) and insoluble (senile plaques) forms, and neuronal loss in affected brain regions (Price and Sisodia, 1994). During the last decade, much effort has been done on targeting clearance of Aβ from the brain of AD patients via the administration of anti-Aβ antibodies (passive vaccination) or Aβ antigens (active vaccination). While several clinical trials using active vaccines based on small B cell epitope of Aβ are ongoing, two major clinical trials on passive vaccination performed in patients with mild to moderate AD have been completed. Based on data from these passive vaccination trials, the scientific community and medical doctors have suggested that treatment must be initiated earlier on, at the prodromal stage, or even earlier. We assume that active immunization is the most feasible approach for the prevention or treatment at the early stage AD, if candidate vaccines are safe, fairly immunogenic in the elderly, and does not activate the potentially harmful autoreactive Th cells in vaccinated subjects. Previously, we reported on an AD epitope vaccines based on the conventional influenza vaccine (Davtyan et al., 2011). Specifically, two chimeric flu viruses expressing either 7 or 10 aa of Aβ42 (WSN-Aβ1–7 or WSN-Aβ1–10) were generated and tested in mice as inactivated vaccines. We demonstrated that this dual vaccine induced therapeutically potent anti-Aβ antibodies and anti-influenza antibodies in mice. This strategy might be beneficial for treatment of AD patients as well as for prevention of development of AD pathology in pre-symptomatic individuals while concurrently boosting immunity against influenza.
It is well known that although yearly influenza vaccines are different due to genetic drift in circulating viruses, they are conserved T and B cell antigenic epitopes in these vaccines. Specifically, the population of conserved memory CD4+ Th cells generated by vaccination and/or previous infection can be boosted by next year vaccination. Based on these observations, as well as on the results generated with other chimeric viruses (Gonzalo et al., 1999, Zheng et al., 2000), including our AD epitope influenza vaccine results (Davtyan et al., 2013) we investigated whether pre-existing memory CD4+ T cells generated by influenza virus vaccination could impact the induction of anti-Aβ antibodies by B cells after one, two or three injections with recombinant flu-Aβ1–10. Contrary to our expectations, this study demonstrates that anti-Aβ humoral responses are compromised in WSN-WT primed mice immunized with WSN-Aβ1–10. These findings are suggestive of the occurrence of carrier induced epitopic suppression (CIES) seen in several conjugate vaccines (Herzenberg and Tokuhisa, 1980, Herzenberg and Tokuhisa, 1982, Jegerlehner et al., 2010, Pobre et al., 2014) or so called original antigenic sin, whereby immune memory is biased toward specific antigenic determinants encountered previously and renders immune responses less effective during sequential exposure to virus variants (Kim et al., 2009).
Section snippets
Mice
Female, 5–6 week-old C57Bl/6 mice were obtained from the Jackson Laboratory (CA). All animals were housed in a temperature- and light cycle-controlled animal facility at the University of California, Irvine (UCI). Animal use protocols were approved by the Institutional Animal Care and Use Committee of UCI and were in accordance with the guidelines of the National Institutes of Health.
Preparation of vaccines
Generation and purification of A/WSN/33 (H1N1) wild-type (WSN-WT) virus as well as chimeric influenza virus
Anti-Aβ humoral responses induced by inactivated chimeric virus WSN-Aβ1–10 are compromised in mice with pre-existing memory against wild-type virus
We first tested the generation of memory Th cells specific to virus in response to vaccination with inactivated WSN-WT (Fig. 1). As expected from earlier studies (Davtyan et al., 2013), after a three-month resting period, mice vaccinated with WSN-WT possessed significantly higher number of influenza specific splenocytes (P < 0.001) producing IFN-γ compared to control animals injected with QuilA only (Fig. 3A). Recall cellular immune responses in immunized mice with pre-existing memory Th cells
Discussion
Current data suggest that the most promising strategy for treatment/prevention of AD is immunotherapy, which via Aβ- and/or tau-specific antibodies could facilitate the clearance of the most toxic forms of β-amyloid and abnormal tau deposits from the brain (Wisniewski and Konietzko, 2008, Schenk et al., 2004, Agadjanyan et al., 2009, Agadjanyan et al., 2005, Cribbs and Agadjanyan, 2005, Weiner and Frenkel, 2006, Sigurdsson, 2009, Ubhi and Masliah, 2011, Gotz et al., 2012). One active vaccine
Conflicts interests
Author(s) declare no financial and commercial conflict of interests. Dr. García-Sastre is named inventor of a patent filed through Mount Sinai School of Medicine that is related to the generation of recombinant influenza A viruses from plasmid DNA.
Acknowledgments
This work was supported by funding from NIH [R01-NS057395 (MGA), R01-AG020241 (MGA) and R01-NS050895 (MGA)] and Alzheimer's Association [IIRG 12-239626 (MGA) and NIRG 13-281227 (HD)]. This work was also partly supported by the Center for Research on Influenza Pathogenesis (CRIP), an NIAID funded Center of Excellence for Influenza Research and Surveillance [CEIRS, contract # HHSN266200700010C (AGS)].
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