AI News, Machine Learning Used to Create an HIV Vaccine
Machine Learning Used to Create an HIV Vaccine
When we think of machine learning it’s usually in the context of robotics—giving an algorithm a large set of input data in order to train it for a certain task like navigation or understanding your handwriting.
For the laymen this is described as a spam filter: using computers to look at large sets of email to develop a complex process for sifting real messages out of the noise.
The task at hand is to look at the genotype of a Controller and compare it with the epitope— a short chain of proteins—in the virus they carry.
The power of machine learning managed to whittle down all the data to a list of the first six epitopes that have the desired dormant-mutation property.
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CD40L-Adjuvanted DNA/Modified Vaccinia Virus Ankara Simian Immunodeficiency Virus (SIV) Vaccine Enhances Protection against Neutralization-Resistant Mucosal SIV Infection
We recently demonstrated that CD40L, a costimulatory molecule for dendritic cells (DCs) and B cells, can serve as an adjuvant for enhancing protection against mucosal challenge with a moderately neutralization-sensitive heterologous simian immunodeficiency virus (SIV), SIVsmE660, in rhesus macaques (1, 2).
The DM group was inoculated intramuscularly at weeks 0 and 8 with 3 mg of a DNA SIV vaccine (DNA/SIV) and boosted with 108 PFU of an MVA SIV vaccine (MVA/SIV) at weeks 16 and 24.
Eight weekly moderate-dose intrarectal challenges with SIVmac251 were initiated at 22 to 24 weeks after the last immunization using 647 50% tissue culture infective doses (TCID50) (1.25 × 107 copies of viral RNA;
This delay in acquisition of infection was not evident in the DM group, although a similar percentage (10 to 20%) of animals in both vaccine groups remained protected after 8 challenges.
Two challenges were sufficient to achieve infection of 50% of the animals in the control and DM groups, whereas 6 challenges were needed for infection of 50% of the animals in the CD40L-adjuvanted group (Fig.
At 12 weeks postinfection (p.i.), the majority of animals (7 out of 9) in the adjuvant group had controlled viremia to below 104 RNA copies/ml, whereas most DM animals (5/8) and all controls (10/10) had virus loads above this level.
These results demonstrate that the CD40L adjuvant not only enhanced protection against acquisition of neutralization-resistant mucosal SIV infection but also provided better long-term control of viral replication and prevention of disease.
We then performed linear epitope-mapping studies using overlapping peptides (15 mers overlapping by 12 amino acids) to define regions of SIV Env targeted by IgG at 2 weeks following the second MVA boost in each animal (Fig.
These findings can likely be extended to IgG levels in rectal secretions because gp140-specific prechallenge rectal and serum IgG levels were highly correlated (P <
We characterized T follicular helper (T-FH) responses and germinal center (GC) B cell responses in nondraining lymph nodes at 2 weeks after the second MVA boost using immunohistochemistry (Fig.
In conclusion, our results show that adjuvanting a DNA/MVA SIV vaccine with CD40L significantly delays acquisition of neutralization-resistant intrarectal SIVmac251 infection, improves long-term viral control, and prevents AIDS.
Interestingly, immune correlate analyses of antibody binding to linear peptides of SIV Env revealed a strong V2 response with narrower binding to the gp41-ID and V1 regions as a correlate of enhanced protection against acquisition of mucosal SIVmac251 infection.
Given the proximity of V1 to V2, one hypothesis is that anti-V1 IgG may interfere with protective functions of anti-V2 IgG (e.g., blocking interaction between the viral envelope and CD4 receptor and clearance of infected cells by antibody-dependent cell-mediated cytotoxicity).
Another hypothesis is that a strong V2 response with narrower binding to non-V2 regions is a surrogate for another immune response, not measured here, that corresponds to a vaccine-induced protective state.
Lentiviral Vector-Based Prime/Boost Vaccination against AIDS: Pilot Study Shows Protection against Simian Immunodeficiency Virus SIVmac251 Challenge in Macaques
This pilot study highlights the potential of nonreplicative HIV-1-derived gene transfer vectors as a candidate AIDS vaccine.
With the exception of one low vaccine responder out of six immunized macaques, the animals showed a strong reduction of viremia during acute infection (from 1 to 4 log10 peak reduction, with a geometric mean of >2 log10), with a concomitant preservation of the CD28+ CD95+ memory CD4+ T cells (Fig.
A long-term follow-up is needed to determine whether vaccinees can control viral replication durably, maintain a large pool of CD28+ CD95+ memory CD4+ T cells and ultimately survive longer than control animals (34, 42).
It was more efficient than the monovalent GAG DNA prime/Ad5 boost vaccine and conferred nearly 1.5 log10 reduction of both peak and chronic phase viremia (up to 1 year follow-up) after repeated low-dose SIVmac239 challenge (56).
In a third study, Watkins and coworkers assessed the protective efficacy of a ADN prime/rAd5 boost vaccine regimen (encoding VIF, VPR, and VPX in addition to GAG, TAT, REV, and NEF) against a repeated mucosal heterologous SIVsmE660 challenge after excluding animals carrying the protective alleles Mamu-A*01, Mamu-B*08, and Mamu-B*17 (55).
A heterologous rAd26 prime/rAd5 boost vaccine regimen expressing only GAG was also reported to afford durable immune control of viral replication (up to 1 year follow-up, with 1.4 and 2.4 log10 reduction of peak and set-point viral loads, respectively) after infection with SIVmac251 of Mamu-A*01− Indian rhesus macaques (31).
Finally, a long-term control of viremia after SIVmac239 challenge was observed after immunization of Indian rhesus macaques with a single cycle SIV (12- and 52-fold lower viremia at the peak and in the chronic phase, respectively) (26).
However, the results we obtained in this first proof-of-concept study make a strong case for the potential of a lentiviral vector-based vaccination against AIDS and suggest that the strategy we developed will achieve increased levels of protection upon further optimization.
Monkeying around with HIV vaccines: using rhesus macaques to define ‘gatekeepers’ for clinical trials
So far we have identified some of the biological and immunological caveats of the rhesus macaque model and learnt that protection against SHIV89.6p and other low-stringency SHIV models is not a good predictor of immunity to HIV in humans.
Although protection of rhesus macaques against SHIV89.6p challenge did not predict protection of humans against HIV transmission, lack of protection by Ad5-based vaccines in rhesus macaques against SIVmac239 challenge did predict the lack of efficacy of this approach in humans.
Thus, a lack of evidence supporting the major assumptions regarding protection and non-protection in rhesus macaques against SIV challenge suggests that the data generated in rhesus macaque challenge models should not be considered a gatekeeper for early clinical advancement (that is, Phase I clinical trials) until the data can be validated using a predefined immunological correlate in humans (BOX 1).
production by enzyme-linked immunosorbent spot (ELISPOT) assay and the expression of lysis-associated molecules such as perforin and granzymes by flow cytometry, for example, are quantifiable and can be further examined as immune gates for the advancement of candidate vaccines into human immunogenicity studies.
Clearly, the levels of vaccine-induced immune responses, including memory responses, should be greater than prior pre-clinically successful vaccine candidates before advancing to the clinic, and so previous efficacy trials have established a benchmark for future vaccines.
especially because cell-free virus, and not cell-associated virus, was recently reported in a conference abstract92 to be the major source of transmitting virus, suggesting a potentially important role for broadly neutralizing antibodies at mucosal sites.
However, convincing antibody data generated in rabbits and other large animal species, which could include non-human primates, showing greater breadth of neutralization must be shown for new antibody approaches to be advanced into Phase I clinical trials (BOX 1).
In light of the STEP trial, the data from rhesus macaque challenge models should not be used as a gatekeeper for Phase I clinical trials, and should be used only for hypothesis-driven basic research until a widely accepted challenge model in rhesus macaques has been validated using a known correlate of protection in humans.
However, high doses of these viruses are typically used to ensure infection, and this practice may overwhelm a potential vaccine response and does not accurately represent the low dose of virus that is associated with natural HIV transmission, which seems to be in the order of one to five transmitted or founder viruses98,99.
This method of virus delivery to rhesus macaques may be a more useful challenge model for evaluating hypothesis-driven research, as the transmission of low numbers of founder viruses may better mimic natural transmission in humans.
However, it is possible that by using low-dose repeated challenge we are setting the bar too low because in monkeys that are kept in otherwise pathogen-free conditions, and in the absence of co-factors that may influence the acquisition of and course of infection, we may see protection that could then disappear in humans harbouring local co-infections.
Thus, low-dose repeated challenge as an administration technique to deliver clinically relevant isolates of SIV may offer a more physiologically relevant regimen for pathogenic SIV challenge experiments100, until an accepted challenge model based on known human correlates can be established.
better understanding of the key genetic and structural differences between the SIV and HIV viruses may help to guide the development of next-generation challenge models and/or chimeric virus strains that may better mimic HIV infection and disease pathology in humans.
Although attempts to generate more HIV-like SHIVs have failed so far112,113, a better understanding of the interactions between the virus and the host cell may help to identify key viral proteins and/or their specific structural regions that are required for replication of HIV in non-human primates.
In summary, Phase I clinical trials of candidate HIV vaccines evaluating safety and predefined immune correlates are crucial for the advancement of HIV studies but should not be continued to efficacy trials unless the vaccine's immunogenicity is shown to be better than that of Ad5-based vaccines in humans.
- On Thursday, January 17, 2019
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