Vaccine for hiv virus

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Medically reviewed by Daniel Murrell, MD. Everything you need to know about cytomegalovirus. Medically reviewed by University of Illinois. Because non-human primates are not susceptible to HIV-1, scientists use a chimeric SHIV in experimental settings because that virus replicates in macaques. After 13 weekly inoculations, two out of seven immunized macaques remained uninfected. The other immunized animals had an overall delay in infection, which occurred, on average, after eight weeks.

In contrast, unimmunized animals became infected on average after three weeks. This may further increase vaccine efficacy and thus lower the number of prime and boost inoculations needed to produce a robust immune response. Reference: P Zhang et al.

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Research Approach. Treatment for Living with Food Allergy. Fungal Diseases. Group A Streptococcal Infections. Vaccine Research. Types of Group A Strep. The platform is flexible and adaptable to various targets, making it perfect for quick responses to new infections [ 55 ]. Nucleic acid-base vaccines such as DNA and mRNA vaccines use the same manufacturing processes to synthesize different encoded antigens.

The same platform can be used to produce a variety of vaccines for different pathogens, utilizing the same production and purification methods and manufacturing facilities; thus, saving enormous costs and reducing considerable time [ 20 ].

Considering all the promises and advantages the mRNA vaccine has brought to the pharmaceutical industry, trials and clinical research have been multiplying in the hope of finding an effective vaccine for prophylactic and therapeutic use against HIV. Unfortunately, many of these experiments have failed. Ex vivo loading of DCs, a delivery system typically employed in the fight against cancer, appears to be the preferable technique for HIV vaccine mRNA delivery [ 21 ].

A clinical trial was conducted in by Gandhi, et al. For this purpose, Zhao, et al. The preliminary results were promising as they demonstrated enough potency, minimal toxicity, with specific antigenic immune responses [ 42 ]. Another trial conducted on macaques by Bogers, et al.

Although it was well-tolerated, safe, and induced a potent cytotoxic T-cell response, it encountered a major throwback with the finding of an additional start codon that modified the entire antigenic protein expression [ 48 , 56 ].

From engineering to producing and manufacturing then clinical testing, the design and production of an effective mRNA vaccine for HIV poses major challenges and obstacles putting the obligation on the scientific community for a better understanding of mRNA-based drug mechanism and delivery strategies as well as proper HIV antigen selection.

It is critical to find the right balance between the immunostimulatory activity of the mRNA vaccine and protein synthesis, as it is possible to overstimulate the innate immune system receptors which would lead to protein destruction. In this scenario, optimizing RNA synthesis manufacturing to eliminate all dsRNA has been linked to increased vaccine effectiveness [ 21 , 55 ]. Because of the structure of RNA, adjuvants can be incorporated into the same molecule [ 57 ].

Finding new adjuvant compounds that can be incorporated into the RNA sequence or vaccine formulation has proved to improve vaccination efficacy, by inducing the desired effectors of an immune response [ 58 ]. The immunogen must be able to elicit a broad and powerful cytotoxic immune response, therefore it must contain epitopes that cover the most common HLA molecules while also targeting viral proteins without immunological escape [ 21 ].

The bad news is that there are hundreds of these molecules that may not work for any vaccine. The existence of a latent reservoir is a key obstacle to an HIV operational cure. As a result, the latent reservoir is an insurmountable barrier [ 60 ]. This is where a new approach came to the surface.

A theory was stipulated to combine a therapeutic vaccine with latency reversal agents LRA and blocking antibodies. LRA are compounds that reactivate the virus, allowing the immune system to attack it. Antibodies designed against the virus, or the receptors utilized by the virus to enter cells are used to prevent the virus from spreading when the latency is broken.

Antibodies designed against the HIV antigen component will prevent the virus from spreading when the latency is broken. Based on this principle, two research projects are making their way to make a potential HIV treatment.

Recruitment will begin in the second half of , in the prospect of finding better answers to the HIV epidemic [ 63 ]. The goal of this review is to shed some light on the history of developments in the mRNA vaccine field as well as the studies that have been conducted to attain an mRNA vaccine for the treatment of HIV.

The safety, efficacy, rapid preparation, and versatility have made mRNA vaccines a preferred platform. Understanding the history and mechanism of HIV and latest mRNA technology advances in terms of stability and delivery systems have led to great advances in the way to develop a vaccine.

Delivery systems such as cationic nanoemulsions and lipid nanoparticles have shown promising results in preclinical studies. Unfortunately, these trials have not yet managed to develop a functional vaccine. The main challenges faced by these trials were high HIV antigenic variations, the presence of a latent HIV reservoir, and difficulty obtaining a broad neutralizing antibody response.

Moreover, more studies need to be conducted in order to determine the right antigen to use and overcome the obstacle of latent reservoirs are necessary for obtaining a balanced yet robust immune response. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein.

All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. The authors have declared that no competing interests exist. National Center for Biotechnology Information , U. Journal List Cureus v. Published online Jul 5.

Author information Article notes Copyright and License information Disclaimer. Corresponding author. Sandeep Padda moc. Accepted Jul 5. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article has been cited by other articles in PMC. Abstract Human immunodeficiency virus HIV is a part of the lentivirus genus of the retroviridae family that incorporates its genome into the host DNA via a series of complex steps.

Keywords: hiv, vaccine, lipid nanoparticles, pandemic, mrna. Table 1 HIV-1 gene-encoded proteins and their functions. Gene Function Gag Encodes p24, p7, and p6 core proteins and p17 matrix protein Pol Encodes for reverse transcriptase, integrase, and protease; Reverse transcriptase transforms viral RNA into DNA, integrase incorporates viral DNA into the chromosomal DNA of the host, and protease cleaves huge gag and Pol protein precursors into their components, all of which are required for viral replication.

Open in a separate window. Figure 1. Steps of HIV-1 replication cycle. Figure 2. Gag: group antigen; Env: envelope; N. Human monocyte-derived dendritic cells Humoral, cellular Env Lipid Nanoparticles Nucleoside-modified, non-amplifying Intradermal Mice, non-human primates Humoral, cellular Gag Cationic nanomicelles Unmodified, non-amplifying Subcutaneous Mice Humoral Env trimeric gp Cationic nanoemulsion Unmodified, self-amplifying Intramuscular Mice, rabbits, non-human primates Humoral, cellular Env trimeric gp Electroporation Unmodified, self-amplifying Intramuscular Mice Humoral, cellular Gag mRNA transfection of dendritic cells Unmodified, non-amplifying N.

In-vitro system Humoral, cellular. Conclusions The goal of this review is to shed some light on the history of developments in the mRNA vaccine field as well as the studies that have been conducted to attain an mRNA vaccine for the treatment of HIV. From to , there have been three major approaches driving HIV-1 vaccine development.

Each of these approaches involved one or more clinical trials and is summarized in Table 1. Though the first two approaches have mostly been concluded, it is worth noting that each approach has been continually reexplored as researchers learn more [ 7 , 12 ]. In the late s, the first approach focused on generating a vaccine that would induce neutralizing antibodies because neutralizing antibodies and their associated subsequent cytotoxic T lymphocyte responses were believed to provide enough protection against HIV Vaccines designed and tested targeted gp or gp HIV-1 envelope proteins [ 13 ].

This was based on the observation that neutralizing antibodies could be produced in response to envelope glycoproteins present on the virus because this had occurred with the recombinant hepatitis B vaccine. This approach mostly ended in , after the VaxGen trials testing gp vaccines produced poor results [ 12 ]. Using a recombinant vector with HIV genes as a vaccine, the virus would produce HIV proteins that would be presented to the immune system via the Class I antigen-presenting pathway [ 14 ].

This approach ended approximately after the STEP trial was terminated [ 12 ]. It is worth noting that no envelope genes were present [ 14 ] because this would allow the immune system to attack the proteins and DNA within the core of the virus. Both clinical trials were ended prematurely because the STEP trial provided no efficacy and did not decrease viral load in participants who contracted HIV.

Hence, it was an example of product failure. The third and current approach is to utilize a heterologous prime-boost to elicit humoral and cell-mediated immune responses [ 13 ].

The prime-boost strategy is based on priming with a virus and boosting with a recombinant protein. A homologous prime-boost is utilized for diphtheria, tetanus, and pertussis DTP and involves administering the same vaccine at intervals to boost the previous responses.

The heterologous prime-boost utilizes the same antigens in different types of vaccines and has been proven to be more immunogenic than the homologous series [ 16 ]. This has been employed in numerous clinical trials, and it has been able to significantly improve the humoral and cellular immune response while simultaneously inducing neutralizing antibodies [ 6 ]. Theoretically, this approach provides a heightened immune response in terms of breadth and depth that is focused on the inserts, not the vectors, and produces unique populations of effector-like memory T-cells that gather at the nonlymphoid organs [ 17 ].

Molecular biology and bioinformatics techniques rapidly evolved and led to the HIV genome sequencing and cloning and identification of structural proteins of the virus [ 12 ]. Since the beginning of HIV vaccine development, it is worth noting the significant changes from the initial recombinant vectors to more effective and safer vectors. This transition to improve recombinant vectors was specifically between the first and second approaches discussed in the history of HIV development section.

Initially, a recombinant vaccinia virus was utilized in , and it posed serious potential concerns [ 17 ]. Individuals who had already received the smallpox vaccine would not mount an appropriate immune response if vaccinated against HIV-1 in the same vector, so receiving this vaccine would be a futile effort. Immunocompromised individuals likely would be severely ill because of the replicating virus [ 17 ]. In , researchers developed MVA, a nonreplicating highly attenuated vaccinia virus with over poxvirus proteins [ 18 ].

It was tested and proven to be safe, inducing a cell-mediated immune response [ 17 ]. Both of these poxviruses are considered to be safe [ 6 ]. Though recombinant vector is an obvious aspect of immunization, it determines immunogenicity and can drastically change the clinical trial results.

An example of this is that plasmid vectors containing Env or Gag in the full-length form have poor immunogenicity and are ineffective. To circumvent this, several clinical trials rely on administering the plasmid with the HIV gene followed by a highly immunogenic recombinant vector [ 2 ]. Given the numerous challenges in HIV-1 vaccine development, scientists doubted whether a vaccine could be generated to provide immunity against this virus. One significant breakthrough that illustrated that a preventative HIV-1 vaccine is possible was the result of the RV trial, obtained in [ 14 ].

Briefly, a summary of the RV trial protocol is as follows. This vector included Env clade E , group-specific antigen gag clade B , and protease pro clade B and is classified as a prime [ 6 ]. This protein boost was a combination of gp clade B Note that this protein was modified.

It is worth noting that both of these components had previously been tested in other trials. The results also found that high levels of Env-specific IgA antibodies were correlated to infection risk in the vaccinated participants of the RV trial.

Haynes et al. Given the unexpected results of RV, there is renewed interest in the role of antibodies outside the classic role of neutralization, and this is particular focused on antibody-dependent cell-mediated cytotoxicity ADCC [ 12 ]. The vaccine regimen was designed to increase the efficacy and immune response duration of RV These modifications from RV included changing the clade present in the vaccine due to regional differences, changing the adjuvant in the protein boost from alum to MF49, and changing the timing of the vaccinations from four injections in six months to five injections over twelve months [ 6 ].

HVTN was terminated prematurely because the independent data and safety monitoring board found that the vaccine was not effective, with approximately the same number of HIV infections in the participants who received the vaccine as the participants who received the placebo [ 6 ]. The rationale behind the study design of HVTN may have led to this product failure in clinical trial. Based on nonhuman primate studies, the alum to MF49 adjuvant change may have contributed to low efficacy in HVTN [ 19 ].

This trial found the regimen to be safe and tolerable, so HVTN proceeded to test its efficacy [ 19 ]. More research is needed to understand why HVTN was projected to be more effective than RV but showed no efficacy [ 6 ]. Researchers have attempted to produce immunogens that induce the immune system to synthesize broadly neutralizing antibodies bNAbs for several years.

Their role is particularly important because bNAbs are able to protect against the strain that the patient has been infected with as well as multiple different immunological strains [ 21 ]. Though Env-specific bNAbs are produced in patients with chronic HIV-1 infections, an antibody must undergo extensive somatic mutation with possible insertions or deletions in the immunoglobin heavy and light chains in the germinal center. BNAbs also typically have a third heavy-chain complementarity-determining region HCDR3 loop, and this feature allows the antibody to combat the Env glycan shield.

Some researchers tracked the evolution of the antibody to its development into a bNAb in an effort to understand the generation of bNAb [ 21 ]. However, despite all the different versions of HIV envelope glycoproteins studied and synthesized, these glycoproteins or fragments have been unable to elicit a neutralizing response to primary isolates of HIV-1 [ 7 ].

The breakthrough that synthesized bNAbs was high throughput single-cell BCR-amplification assays [ 10 ]. This was completed by separating HIV-1 Env-reactive memory B cells from antigen-specific B cells, from plasma cells, and from clonal memory B cell cultures [ 20 ]. To investigate whether these bNAbs could induce a protective immune response in human subjects with HIV-1 infections, two early phase clinical trials were completed.

Caskey et al. Lynch et al.