HIV vaccine development
Mar 24, · The vaccines did not prevent infection, but they protected the pigs from developing severe symptoms, much like the observations made when primates were tested with candidate COVID vaccines. Apr 14, · BOSTON — Researchers are studying COVID vaccine technology as a potential opportunity to develop vaccines for chronic and terminal illnesses like HIV and cancer. Some scientists believe mRNA technology is offering a promising development in decades’ worth of efforts.
Judy Dodd, who lives in New York City, is one of them. She spent nearly a year plagued by wome, shortness what was indira gandhi famous for breath, extreme fatigue and problems with smell, among other symptoms. She says she vaccnies that this "slog through life" was going to be her new normal. And she's not alone.
As the U. It's the latest clue in the immunological puzzle of long COVID, a still poorly understood condition that leaves some who get infected with wide-ranging symptoms months after the initial illness. The notion that a vaccine aimed at preventing the disease may also be a treatment has sparked optimism among patients, and scientists who study the post-illness syndrome are taking a close look at these what are some potential aids vaccines. While promising, it's still too early to know just how many people with long COVID are feeling better as a result of being vaccinated and whether that amounts to a statistically meaningful difference.
In the meantime, Iwasaki and other researchers are beginning to incorporate this question into ongoing studies of long-haulers by monitoring their symptoms pre- and post-vaccination and collecting blood samples to study their immune response. There are several leading theories for why vaccines could alleviate the symptoms of long COVID: It's possible the vaccine clears up leftover virus or fragments, interrupts a damaging autoimmune response, or in some other way "resets" the immune system.
Steven Deeks of the University of California, San Francisco, who is also studying the long-term impacts of the coronavirus on some patients. Before getting the vaccine, Dodd, who's in her early 50s, says she felt like she had aged 20 years. She had trouble ade to work and even simple tasks left her with a crushing headache and exhaustion.
After she got her first dose of the Whag vaccine what is the scientific name for rose January, many of Dodd's symptoms flared up, so much what size is a single bed quilt cover that she almost didn't get her second dose. But she did — and a few days later, she noticed her energy was back, breathing was easier and soon even her problems with smell were resolving.
The sun was out," she says. In the absence of large studies, researchers are culling what information they can from patient stories, informal surveys and clinicians' experiences.
Among the patients of Dr. Daniel Griffin at Columbia University Medical Center in New York City, "brain fog" and gastrointestinal problems are two of the most common symptoms that seem to resolve post-vaccination.
Now, he believes the number may be higher, as more patients receive their second dose and see further improvements. A small U. Indeed, doctors and online surveys also have found that a smaller fraction of patients say their symptoms afe after vaccination, although generally doctors continue to advise that those with long COVID get vaccinated to protect against reinfection.
There are several theories for why vaccines could help some patients — each relying on different physiological understandings of long COVID, which manifests in a variety of ways. Some people have fast resting heart rates and intolerance to exercise. Others suffer primarily from cognitive problems, or some combination of symptoms like exhaustion, trouble sleeping and issues with smell and taste, he says. One theory is that people who are infected never fully clear the coronavirus, and a viral "reservoir," or fragments of the virus, persist in parts of the body and cause inflammation and long-term symptoms, says Aida, the Yale immunologist.
According to that explanation, the vaccine might induce an immune response that gives the body extra firepower to beat back the residual infection. Griffin at Columbia Medical Center says this "viral persistence" idea is supported by what he's seeing in his patients and hearing from other researchers and clinicians.
He says patients seem to be improving after receiving any of the four different COVID vaccines, generally about "two weeks later when it looks like they're having what would be an effective, protective response.
Another possible reason that some patients improve comes from the understanding of long COVID as an autoimmune condition, in which the how to hack using ip immune cells end up damaging its own tissues.
A vaccine could hypothetically kick into what are some potential aids vaccines the "innate immune system" and "dampen the symptoms," but only temporarily, says Iwasaki, who has studied the role of harmful proteinscalled autoantibodies, in COVID This self-destructive immune response happens in a subset of COVID patients while they are ill, and the autoantibodies produced can circulate for months later. Another theory is that the infection has vwccines the immune system in some other way and caused chronic inflammation, perhaps like chronic fatigue syndrome, Wherry says.
In that scenario, the vaccination might somehow "reset" the immune system. With more than 53 million people fully vaccinated in the U. Real data — and more answers on how the vaccine might help — may come as soon as the next few months, says Topol, of the Scripps research institute.
Listen to story Download this story 3MB. Patient stories offer hope Before getting the vaccine, Dodd, who's in her early 50s, says she felt like she had aged 20 years. But not all clinicians are seeing the potenyial level of improvement. Dome are patients feeling better?
Oct 20, · But the Ad5 strain used in a potential HIV vaccination a decade ago was found to make some men more vulnerable to HIV in placebo-controlled trials, according to Science Magzine. The COVID pandemic has resulted in misinformation and conspiracy theories about the scale of the pandemic and the origin, prevention, diagnosis, and treatment of the chesapeakecharge.com information, including intentional disinformation, has been spread through social media, text messaging, and mass chesapeakecharge.comlists have been arrested for allegedly spreading fake news about the pandemic. Jan 12, · mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential .
Therapeutic considerations and challenges include scaling up good manufacturing practice GMP production, establishing regulations, further documenting safety and increasing efficacy. Important future directions of research will be to compare and elucidate the immune pathways activated by various mRNA vaccine platforms, to improve current approaches based on these mechanisms and to initiate new clinical trials against additional disease targets.
However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans.
This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use. Vaccines prevent many millions of illnesses and save numerous lives every year 1.
As a result of widespread vaccine use, the smallpox virus has been completely eradicated and the incidence of polio, measles and other childhood diseases has been drastically reduced around the world 2.
Conventional vaccine approaches, such as live attenuated and inactivated pathogens and subunit vaccines, provide durable protection against a variety of dangerous diseases 3. Despite this success, there remain major hurdles to vaccine development against a variety of infectious pathogens, especially those better able to evade the adaptive immune response 4.
Moreover, for most emerging virus vaccines, the main obstacle is not the effectiveness of conventional approaches but the need for more rapid development and large-scale deployment.
Finally, conventional vaccine approaches may not be applicable to non-infectious diseases, such as cancer. The development of more potent and versatile vaccine platforms is therefore urgently needed. Nucleic acid therapeutics have emerged as promising alternatives to conventional vaccine approaches.
The first report of the successful use of in vitro transcribed IVT mRNA in animals was published in , when reporter gene mRNAs were injected into mice and protein production was detected 5. A subsequent study in demonstrated that administration of vasopressin-encoding mRNA in the hypothalamus could elicit a physiological response in rats 6.
However, these early promising results did not lead to substantial investment in developing mRNA therapeutics, largely owing to concerns associated with mRNA instability, high innate immunogenicity and inefficient in vivo delivery.
Instead, the field pursued DNA-based and protein-based therapeutic approaches 7 , 8. Over the past decade, major technological innovation and research investment have enabled mRNA to become a promising therapeutic tool in the fields of vaccine development and protein replacement therapy.
The use of mRNA has several beneficial features over subunit, killed and live attenuated virus, as well as DNA-based vaccines. First, safety: as mRNA is a non-infectious, non-integrating platform, there is no potential risk of infection or insertional mutagenesis. Additionally, mRNA is degraded by normal cellular processes, and its in vivo half-life can be regulated through the use of various modifications and delivery methods 9 , 10 , 11 , The inherent immunogenicity of the mRNA can be down-modulated to further increase the safety profile 9 , 12 , Second, efficacy: various modifications make mRNA more stable and highly translatable 9 , 12 , Efficient in vivo delivery can be achieved by formulating mRNA into carrier molecules, allowing rapid uptake and expression in the cytoplasm reviewed in Refs 10 , Third, production: mRNA vaccines have the potential for rapid, inexpensive and scalable manufacturing, mainly owing to the high yields of in vitro transcription reactions.
The mRNA vaccine field is developing extremely rapidly; a large body of preclinical data has accumulated over the past several years, and multiple human clinical trials have been initiated. In this Review, we discuss current mRNA vaccine approaches, summarize the latest findings, highlight challenges and recent successes, and offer perspectives on the future of mRNA vaccines.
The data suggest that mRNA vaccines have the potential to solve many of the challenges in vaccine development for both infectious diseases and cancer.
The mRNA is thus engineered to resemble fully processed mature mRNA molecules as they occur naturally in the cytoplasm of eukaryotic cells. Complexing of mRNA for in vivo delivery has also been recently detailed 10 , Thus, a great variety of in vitro and in vivo transfection reagents have been developed that facilitate cellular uptake of mRNA and protect it from degradation. Once the mRNA transits to the cytosol, the cellular translation machinery produces protein that undergoes post-translational modifications, resulting in a properly folded, fully functional protein.
This feature of mRNA pharmacology is particularly advantageous for vaccines and protein replacement therapies that require cytosolic or transmembrane proteins to be delivered to the correct cellular compartments for proper presentation or function.
IVT mRNA is finally degraded by normal physiological processes, thus reducing the risk of metabolite toxicity. Various mRNA vaccine platforms have been developed in recent years and validated in studies of immunogenicity and efficacy 18 , 19 , Highly efficient and non-toxic RNA carriers have been developed that in some cases 21 , 22 allow prolonged antigen expression in vivo Table 1. Some vaccine formulations contain novel adjuvants, while others elicit potent responses in the absence of known adjuvants.
The following section summarizes the key advances in these areas of mRNA engineering and their impact on vaccine efficacy. This topic has been extensively discussed in previous reviews 14 , 15 ; thus, we briefly summarize the key findings Box 1.
These regulatory sequences can be derived from viral or eukaryotic genes and greatly increase the half-life and expression of therapeutic mRNAs 23 , The poly A tail also plays an important regulatory role in mRNA translation and stability 25 ; thus, an optimal length of poly A 24 must be added to mRNA either directly from the encoding DNA template or by using poly A polymerase. The codon usage additionally has an impact on protein translation.
Replacing rare codons with frequently used synonymous codons that have abundant cognate tRNA in the cytosol is a common practice to increase protein production from mRNA 29 , although the accuracy of this model has been questioned Enrichment of G:C content constitutes another form of sequence optimization that has been shown to increase steady-state mRNA levels in vitro 31 and protein expression in vivo Although protein expression may be positively modulated by altering the codon composition or by introducing modified nucleosides discussed below , it is also possible that these forms of sequence engineering could affect mRNA secondary structure 32 , the kinetics and accuracy of translation and simultaneous protein folding 33 , 34 , and the expression of cryptic T cell epitopes present in alternative reading frames All these factors could potentially influence the magnitude or specificity of the immune response.
A number of technologies are currently used to improve the pharmacological aspects of mRNA. The various mRNA modifications used and their impact are summarized below. Exogenous mRNA is inherently immunostimulatory, as it is recognized by a variety of cell surface, endosomal and cytosolic innate immune receptors Fig. Depending on the therapeutic application, this feature of mRNA could be beneficial or detrimental.
It is potentially advantageous for vaccination because in some cases it may provide adjuvant activity to drive dendritic cell DC maturation and thus elicit robust T and B cell immune responses. However, innate immune sensing of mRNA has also been associated with the inhibition of antigen expression and may negatively affect the immune response 9 , Although the paradoxical effects of innate immune sensing on different formats of mRNA vaccines are incompletely understood, some progress has been made in recent years in elucidating these phenomena.
A non-exhaustive list of the major known RNA sensors that contribute to the recognition of double-stranded and unmodified single-stranded RNAs is shown. Unmodified, unpurified part a and nucleoside-modified, fast protein liquid chromatography FPLC -purified part b mRNAs were selected for illustration of two formats of mRNA vaccines where known forms of mRNA sensing are present and absent, respectively.
The dashed arrow represents reduced antigen expression. PowerPoint slide. Studies over the past decade have shown that the immunostimulatory profile of mRNA can be shaped by the purification of IVT mRNA and the introduction of modified nucleosides as well as by complexing the mRNA with various carrier molecules 9 , 13 , 36 , As a mimic of viral genomes and replication intermediates, dsRNA is a potent pathogen-associated molecular pattern PAMP that is sensed by pattern recognition receptors in multiple cellular compartments Fig.
Thus, appropriate purification of IVT mRNA seems to be critical for maximizing protein immunogen production in DCs and for avoiding unwanted innate immune activation. Single-stranded oligoribonucleotides and their degradative products are detected by the endosomal sensors Toll-like receptor 7 TLR7 and TLR8 Refs 40 , 41 , resulting in type I interferon production Crucially, it was discovered that the incorporation of naturally occurring chemically modified nucleosides, including but not limited to pseudouridine 9 , 43 , 44 and 1-methylpseudouridine 45 , prevents activation of TLR7, TLR8 and other innate immune sensors 46 , 47 , thus reducing type I interferon signalling Nucleoside modification also partially suppresses the recognition of dsRNA species 46 , 47 , These advances in understanding the sources of innate immune sensing and how to avoid their adverse effects have substantially contributed to the current interest in mRNA-based vaccines and protein replacement therapies.
In contrast to the findings described above, a study by Thess and colleagues found that sequence-optimized, HPLC-purified, unmodified mRNA produced higher levels of protein in HeLa cells and in mice than its nucleoside-modified counterpart Additionally, Kauffman and co-workers demonstrated that unmodified, non-HPLC-purified mRNA yielded more robust protein production in HeLa cells than nucleoside-modified mRNA, and resulted in similar levels of protein production in mice The immunostimulatory properties of mRNA can conversely be increased by the inclusion of an adjuvant to increase the potency of some mRNA vaccine formats.
These include traditional adjuvants as well as novel approaches that take advantage of the intrinsic immunogenicity of mRNA or its ability to encode immune-modulatory proteins. Self-replicating RNA vaccines have displayed increased immunogenicity and effectiveness after formulating the RNA in a cationic nanoemulsion based on the licensed MF59 Novartis adjuvant In this case, the antigen is expressed from a naked, unmodified, sequence-optimized mRNA, while the adjuvant activity is provided by co-delivered RNA complexed with protamine a polycationic peptide , which acts via TLR7 signalling 52 , This vaccine format has elicited favourable immune responses in multiple preclinical animal studies for vaccination against cancer and infectious diseases 18 , 36 , 55 , A recent study provided mechanistic information on the adjuvanticity of RNActive vaccines in mice in vivo and human cells in vitro Potent activation of TLR7 mouse and human and TLR8 human and production of type I interferon, pro-inflammatory cytokines and chemokines after intradermal immunization was shown Efficient in vivo mRNA delivery is critical to achieving therapeutic relevance.
Exogenous mRNA must penetrate the barrier of the lipid membrane in order to reach the cytoplasm to be translated to functional protein. There are two basic approaches for the delivery of mRNA vaccines that have been described to date.
First, loading of mRNA into DCs ex vivo , followed by re-infusion of the transfected cells 58 ; and second, direct parenteral injection of mRNA with or without a carrier. Ex vivo DC loading allows precise control of the cellular target, transfection efficiency and other cellular conditions, but as a form of cell therapy, it is an expensive and labour-intensive approach to vaccination.
Direct injection of mRNA is comparatively rapid and cost-effective, but it does not yet allow precise and efficient cell-type-specific delivery, although there has been recent progress in this regard Both of these approaches have been explored in a variety of forms Fig. Ex vivo loading of DCs. DCs are the most potent antigen-presenting cells of the immune system. Additionally, DCs may present intact antigen to B cells to provoke an antibody response DCs are also highly amenable to mRNA transfection.
For these reasons, DCs represent an attractive target for transfection by mRNA vaccines, both in vivo and ex vivo. Although DCs have been shown to internalize naked mRNA through a variety of endocytic pathways 61 , 62 , 63 , ex vivo transfection efficiency is commonly increased using electroporation; in this case, mRNA molecules pass through membrane pores formed by a high-voltage pulse and directly enter the cytoplasm reviewed in Ref.
This mRNA delivery approach has been favoured for its ability to generate high transfection efficiency without the need for a carrier molecule. DCs that are loaded with mRNA ex vivo are then re-infused into the autologous vaccine recipient to initiate the immune response. Most ex vivo -loaded DC vaccines elicit a predominantly cell-mediated immune response; thus, they have been used primarily to treat cancer reviewed in Ref. Injection of naked mRNA in vivo.
Naked mRNA has been used successfully for in vivo immunizations, particularly in formats that preferentially target antigen-presenting cells, as in intradermal 61 , 65 and intranodal injections 66 , 67 , Notably, a recent report showed that repeated intranodal immunizations with naked, unmodified mRNA encoding tumour-associated neoantigens generated robust T cell responses and increased progression-free survival 68 discussed further in Box 2.
Physical delivery methods in vivo.