Research on an AIDS vaccine has been ongoing for years. Very few positive results have been achieved. More recently the focus has been on broadly neutralizing antibodies (bNAbs). Broadly neutralizing antibodies show up naturally in a person infected with HIV only later in the infection. These antibodies have been shown to be effective in neutralizing the HIV virus but only if they appear early in HIV infection.The idea now is to try to develop a vaccine which elicits bNAbs.
In your investigation of this problem, determine why the vaccines developed in the past have largely been ineffective in prevening AIDS.
Also, answer the following questions.
Why are bNAbs effective?
Why are they more effective in early infection?
Why are they produced later in HIV infection?
Do you think an effective AIDS vaccine will be developed?
Could bNAbs be isolated and purified and used in a passive vaccine?
due Oct 20
Different from other viruses, HIV-specific immune response is inadequate and past vaccines didn’t’ really work because of several factors as: ability of HIV to establish latency (“hiding” in host cells), the diversity and mutability of the virus, the ability of AIDS viruses to avoid immune responses by masking its own more conserved components, and the destruction and dysfunction the virus can cause in immune system cells.
ReplyDeleteScientists are trying to develop a vaccine which induces an infected person to produce bNAbs. bNAbs are naturally produced by the HIV-infected individuals and it is effective since this antibody binds and neutralize most of the circulating HIV strains.
bNAbs would be more effective in early infection because it would probably have a faster action, since HVI virus mutates over time. But usually it acts after Env proteins of the virus activate B cells at the time of acute infection. Researches show that the diversification of the Env protein preceded the appearance of bNAb response.
Honestly, I think there is already a vaccine for AIDS, but it’s not economically viable for government. Since AIDS is a pandemic illness, the government would have to make it reachable for the population by a cheap price or even free for third world countries (which have the most part of individuals infected). I’m totally aware of conspiracies and I’m not saying this is a fact, but I do think this is a possibility. I do believe there is or there will be a vaccine or even another kind of way for fighting against AIDS.
There is a problem in introducing isolated bNAbs from an infected-individual to another infected-individual who doesn’t produce bNAbs: these antibodies recognize the body’s own tissues, which are normally eliminated by the immune system. However, scientists are working on isolating bNAbs and are trying to make it useful for producing a vaccine.
HIV is still considered a major issue to human health around the world. The reason why HIV is so hard to contain is the inability to come up with a vaccine to neutralize it. However, in recent studies, broadly used neutralizing antibodies (bNAbs) were discovered and can help with passive immunity. The bNAbs were aimed at targeting a diverse group of epitopes, especially the glycoprotein of HIVs. The immunogens that recognize the bNAbs, could lead to helpful discovery of useful agents to develop (hopefully) a vaccine. bNAbs are useful in this case. According to research- the ability of bNAbs to neutralize different subtypes of HIV, bNAbs targeted the CD4 binding site of Env protein.
ReplyDeleteAny kind of treatment or progression of any disease that is taken care of early on is always better.
Currently, there is no HIV vaccine, but many researchers are conducting different ways to hopefully create one-different evidence shows that this is possible, however. I sure hope, will the advancements in technology nowadays, that a vaccine may become possible for individuals with AIDS. ABCNews, recently released an article (9/12/2013) stated: Scientists claim success for vaccine tested on HIV-type virus- it mentions, "Scientists in the United States have tested a vaccine on monkeys that appears to be effective in preventing the simian equivalent of HIV. Research published in the journal Nature showed the vaccine enabled half the monkeys tested to clear from their bodies an infection of the Simian Immunodeficiency Virus (SIV). The vaccine was effective in nine of the 16 monkeys inoculated. The scientists say at first the infection began to establish and spread, but then the monkeys' bodies started to respond by searching out and eradicating all signs of SIV. The monkey's that responded successfully were still free of infection between one-and-a-half and three years later. The team says, they are trying to establish why the vaccine only worked in half the monkey's tested, hope this could pave the way for human clinical trials in two years after stringent safety tests." I truly believe science and technology will eventually lead to results that can be felt worldwide and in a positive way.
bNAbs can be used and isolated and used for passive immunity (they are usually isolated from HIV-infected individuals and in this case, even more potent). One problem though, these particular antibodies recognize an individual's own body tissues- which then are eliminated by the immune system. But, this is a successful step for scientists, trying to isolate and test the outcomes with each trial. I truly believe, with time, that scientists will come up with an effective vaccine for HIV-infected persons.
-Peter F.
First, the HIV virus is highly mutable, evading the immune system (thus, it’s great success) and making it difficult to produce an antibody specifically against it and a vaccine that mimics it broadly enough to induce a response, leading to ability to neutralize when exposed again. There are also many strains of HIV to begin with. Additionally, the viral protein envelope has many mechanisms to elude the immune system, masking its virility and thus bypassing the inducement of an immune response. Animal models have also made it difficult to develop a vaccine, as there is not a good case that is similar to humans. Actually, vaccines found effective to a degree in animals have shown no results when injected in humans (they still contracted the virus upon later exposure).
ReplyDeleteBecause HIV is highly mutable and there are many strains, a broadly neutralizing Ab is effective in recognizing and neutralizing the broad range of HIV viruses present in the body. Usually, Abs are highly specific (Ag-Ab binding highly specific due to structure) and thus only recognize specific antigens. Once an Ab is produced against a specific HIV strain however, it may mutate, or other strains may be introduced (in highly affected regions), leaving the Ab fighting the lesser strain, or unable to recognize any Ag at all. Thus, Abs able to recognize many antigens are much more effective against the HIV virus, able to respond to varying mutated strains.
bNAbs are more effective early as the HIV virus has had less time to mutate (more mutations the longer present). Also, there would be a lower concentration in the body early on, again allowing the bNAbs to more effectively neutralize them completely.
It has been shown in some studies that they are associated with autoimmune diseases, in that they recognize “self” proteins, inducing an immune response against the host. Perhaps, as the disease progressed, the body was unable to inhibit the production of these Abs which it normally did. Other studies however show it is a natural later stage in the bodies fight against the HIV virus, but sadly comes too late usually, as a last measure after the HIV virus is too mutated to be recognized by even the bNAbs.
I think it is possible, but time must be taken. The animal model testing difficulties, the prevalence in third world countries (difficulties with government, with transportation, with funding, etc.) are quite monumental. Though a vaccine may possibly be produced, it would certainly be difficult to distribute it.
Again, there is the difficulty of the Abs recognizing self and inducing a response against self. But, it is possible to isolate and purify the bNAbs from an infected host, and injected into others, giving hope to the finding of an effective vaccine. - T.A.
Vaccines against HIV have done very little in protecting against HIV. The main issue is that the HIV virus has capabilities to change very rapidly. This is the primary purpose that HIV is so deadly in that it can avoid destruction by the immune system. Broadly Neutralizing antibodies or bNAbs are effective in that they also can attack a wide variety of antigens, as the name suggests, neutralize a broad spectrum of viruses. These bNAbs are able attack the HIV virus and eliminate it as it changes without allowing the virus to mutate and repopulate in a different form. It is suggested that the bNAbs’ PG9 and PG16 target epitopes on the antigens of HIV that do not change or mutate thus allowing the bNAbs to be broad and attack a wide range of HIV strains. bNAbs are not created initially as the body only creates antibodies for previous versions of the virus and is behind HIV as it mutates. bNAbs have to have time to mature and they take time before they become effective against HIV. That is the main shortfall that vaccine research is trying to overcome as they attempt to create a vaccine to induce bNAbs to be made and also to mature rapidly.
ReplyDeletebNAbs are unique antibodies which are difficult to induce in most humans. The problematic side of this fact is that the reason(s) for difficulty in inducing production of bNAbs is(are) poorly understood. A problem that is little understood is difficult, near impossible, to solve. If one doesn't understand the factors involved, the hurdles that need be overcome, where does one start in proposing solutions? Therefore, bNAbs must first be better understood - how they function, why they are induced late in HIV infection, why they are prohibited early in HIV infection or in non-infected individuals, and etc.
ReplyDelete"Thus, defining impediments to their routine induction is critical to successful HIV-1 vaccine development" (Verkoczy, Role of immune mechanisms in induction of HIV-1 broadly neutralizing antibodies, Curr Opin Immunol., 2011).
Many suggestions have been made regarding the difficulty of inducing bNAbs, many regarding the nature and structure of the envelope proteins of the HIV-1 Envelope. Another hypothesis states that B cells "are sufficiently autoreactive to trigger tolerance mechanisms that eliminate or modify bNAb self-reactivity" (Verkoczy).
Determining the validity of the various hypotheses and how to overcome them to be able to regularly induce the production of bNAbs early in the HIV infection is crucial to developing a vaccine based upon bNAbs, or in proving their ineffectiveness as a vaccine, and so allowing reallocation of resources and brain storming to continue attempting to find an HIV vaccine. -T.A.
Why are bNAbs effective?
ReplyDeleteIt seems that bNAbs are effective because like their name implies, they are able to pick up a broad range of possibly variable antigens on the HIV virus. HIV-1 is so deadly because it is constantly changing and there are many forms, thus causing evasion of the adaptive immune system. Two new antibodies (PG9 and PG16)found by the International Aids Vaccine Initiative (IAVI) are able to target and bind to a region of the spikes on HIV (envelope protein or ENV) that are used to infect cells. This region contains glycoproteins (gp120 and gp41) that are usually highly variable and continue to change. However, PG9 and PG16 are able to recognize a part of gp120 that does not seem to change.
It seems that more bNAbs are produced later in HIV infection because they need time to mutate their structure (called affinity maturation) to gain their ability to bind to the variable parts of HIV.
It seems as though one of the problems with the adaptive immune system in recognizing HIV antigens is that there is such a low affinity for the ENV proteins due to the constant changing of the HIV virus. Thus, as others have mentioned, the B cells that produce bNAbs are able to mutate through a process called affinity maturation to develop plasma cells that produce higher affinity antibodies on the one hand, and destroy plasma cells that are only producing low affinity antibodies (apoptosis) on the other. It would appear that the affinity has a lot to do with binding to the regions on the virus that are conserved or similar among each virus.I thought that this video was pretty good at explaining it and it had good graphics! http://www.youtube.com/watch?v=qGsyBwDVnTU
ReplyDeleteThe bNAbs identified to date are effective in early infection because they target diverse epitopes, especially on the HIV-1 envelope glycoprotein called Env, and they can control the spread of many HIV-1 subtypes. They are produced later in the HIV infection because they must go through a lengthy development process. They have found that B cells need to come in repeated contact with the virus over years to accumulate changes, or mutations, in their antibody genes that enable their antibodies to bind epitopes on the HIV Envelope more efficiently. Eventually, this so-called affinity maturation process leads to B cells that can produce HIV-specific bNAbs that are very different from their unmutated precursors.
ReplyDeletehttp://www.vaxreport.org/Back-Issues/Pages/Understanding-How-a-Vaccine-May-be-Designed-to-Induce-Broadly-Neutralizing-Antibodies.aspx
- JLo
DeletePrevious vaccines have been ineffective because HIV rapidly replicates and mutates. The immune system cannot keep up with these mutations: it cannot make antibodies to the virus before it mutates again.
ReplyDeleteNaturally produced bNabs are made later because by then, the HIV has pervaded the system enough to be recognized and antibodies made against it. It is more effective earlier on in the infection because the antibodies can eliminate the fewer infected cells. Another aspect of it is that HIV infects B cells, so later on in the infection, many B cells have been destroyed so the body's ability to make antibodies and combat the virus is compromised.
After reading some of the articles relating to HIV and the work toward a vaccine, it appears that a vaccine could be developed. HIV is such a huge issue today as it has claimed and continues to claim numerous lives. With people so away of the devastating ability of HIV much research has been devoted to find a cure. Since HIV is a clear foreign agent with specific antigens, I believe some cure will be developed in the future to prevent HIV from taking lives.
ReplyDeleteAs far as using bNAbs as a passive vaccine, I do not think that would be the best and easiest way to proceed. Since the bNAbs have been found to need to mature, there are most likely many factors relating to their maturation which we do not know about. Because of this maturation of the antibodies, I believe passive vaccination is not the best way to proceed.
bNAb's are effective, because they can identify a large number of HIV virus and their mutations than a normal antibody produced against HIV. HIV has such a high mutation rate, it will make a bNAb vaccine be more readily able to destroy the different variations of the HIV virus, instead of a single variation of normal antibody. However a person would need to be vaccinated early on in order to stop the infection from the HIV virus and its variants as once infected the virus will continue to progressing even with bNAb's
ReplyDeleteDo you think an effective aids vaccine could be developed?
ReplyDeleteI think its possible with bNAb's, the HIV virus has an enormous amounts of variants produced, the reason previous vaccination don't work is because the antibody could only protect an individual from a certain number of variants, before the virus mutates into a structure that can escape antibody detection and then spread through infection. However bNAb's also have enormous amount of variations that can detect the HIV virus, because it also has a high mutation rate, I could see it working as vaccine if it is able to account for all the variants, a idea on how this could work is if we force exposure over a enormous amount of variants of the HIV to the bNAb's. We could have an enormous amount of different mutations of bNAb's that can be used early on to account for the HIV virus at the early stages of infection to counteract for the viruses high mutation rate.
Why are they produced later in the HIV infection?
ReplyDeletebNAb's are produced later in the HIV infection by the body's attempt to develop a countermeasure against the HIV virus, however the reaction of the immune system is too slow against the speed and the magnitude of the different HIV variants developed which means that the bNAb's are produced too late in regards to the infection of the HIV virus.
I actually found an article that said it was modified bNabs that recognize self-tissue. Naturally produced antibodies were not likely to be autoreactive (attack the body's tissues). The problem with using naturally produced bNabs is that they are not as potent as the modified versions. However, isolating enough pure antibody to be effective appears to be a problem.
ReplyDeleteIn the same article (http://www.iavireport.org/Blog/archive/2013/02/13/on-passive-immunization-and-the-effects-of-gender-and-bmi-on-vaccination.aspx), it was mentioned that human vaccine trials have been conducted. I was not aware that this research was so advanced, but it seems to suggest that an effective vaccine may not be too far off. Especially since there has been rapid technological growth over the past few years that has helped speed up this research--perhaps in years to come, even if it is found to take a different direction, development may move faster.
Why are bNAbs effective?
ReplyDeleteIt looks like bNAbs are effective because they recognize a variety of epitopes on HIV. HIV produce different proteins as they replicate and as they replicate they also produce different epitopes. Also HIV genome changes quickly during replication, it changes too fast for human immune system to destroy it in time. So if an antibody recognizes one epitope it will not be able to recognize the other. For this reason the early stage antibodies are in effective to destroy the HIV virus. bNAbs can target more than just one epitope and recognize multiple epitopes. bNAbs also have very different physical shape which effect the antibody-antigen binding and effect the structural domain. Also they are more effective because they are produced so later in stage so they can accumulate a diverse types of binding sites. bNabs have high level of mutations so as they replicate all these mutations accumulate eventually to make one very powerful antibody with variety of possible ways to neutralizing the virus.
In the early stages it was thought that the mutations were in antigen-recognition site but later found out by Liao et al that these changes happen in structural region. Also these changes were not incidental but were very critical in neutralizing the virus. These changes also made the antibody more potent against the virus by providing more than one way of neutralizing the virus, possibly by by expanding the antigen-recognition footprint, by subtly altering binding-loop positioning, and maybe by changing the conformational dynamics of antibody–antigen binding.
Why are they produced later in HIV infection?
According to http://www.nejm.org/doi/full/10.1056/NEJMcibr1304437 bNAbs have high level of mutations that effect the binding site. And these changes by mutations accumulate over the exposure of infection. This could be the reason why bNAbs are produced in later stage of infection. HIV virus replicates rapidly and so it also diversifies rapidly. So as the virus diversifies rapidly the antibodies have to diversify rapidly as well and so we have a very potent antibody made bNAbs that can neutralize the infection.
Why are they more effective in early infection?
These would definitely be very effective in early infection if they were available. But these are created in later stage because they have to adapt and change to be able to bind to all the variety of regions on the virus. So from what I learned are bNAbs are not available in the early stage of infection but would be very effective in destroying the virus if were available because of all the wide variety of epitopes they can attach to.
Do you think an effective AIDS vaccine will be developed?
I think the vaccine for HIV will be developed. As more research is done on HIV virus, we can understand now to neutralize this better. Just as a couple of years ago we had no cure to this virus and all antibodies failed to destroy HIV virus but today we have bNAbs that possible can neutralize this infection. As we learn more about the function of this antibody and the function of the HIV virus we can get close and close to developing a cure to HIV virus.
Could bNAbs be isolated and purified and used in a passive vaccine?
According to most of the articles I read researchers were able to isolate bNAbs. So I think researchers will be able to purify it and use it as a passive vaccination.
Priyank Puranik
HIV is a very unique virus because there are no known cases to date where the person infected has naturally recovered. When looking at the history of vaccinations, the key process in trying to prevent the infection was based on the immune system’s ability to remember and evade the infection. HIV has many different mechanisms to hide from the immune system and become latent in the cells. This is just one of the reasons it has been so hard to create a vaccine. Other problems are the mutation rate of the virus and the inability to create a testable animal strain similar to humans, as previously stated. Without the ability to test and research accurately with animals, it makes the process more difficult to find out more about the virus and create a testable vaccine. Yet, I think it is possible to create a vaccine.
ReplyDeleteOne trial run done that seems promising is the RV144 trial done in Thailand. It lasted 6 years with 16,000 participants. They used a prime-boost combination of vaccines. The first was the prime vaccine which used a canarypox virus that had inserted genes for antigenic proteins from HIV subtypes B and E and was intended to stimulate cell-mediated immunity. The second vaccine was a boost intended to stimulate antibody response from B-cells and contained genetically engineered antigenic surface protein from HIV. These both were used in combination since the boost was originally tested, but failed. The combination yielded 31% less HIV infections from people who received this vaccine in the trial than the people who received placebo. This trial still does not have the highest results for vaccination, but this gives researchers headway into understanding the virus and creating a better vaccine.
bNAbs are so effective because they can neutralize a broad range of strains for the HIV virus. They code for these different antigens through a unique process of mutation called affinity maturation. The problem with this is that it seems to take years for these bNAbs to mature to the level of mutation that can neutralize the different strains and only about 20% of people infected create these antibodies. This is also a reason they are more effective earlier on. As they get the bNAbs into their system, they can continue to mature and mutate to keep neutralize the different strains. They also have fewer strains to neutralize and do not have to be as mature. The later the bNAbs are given, the more they need to mutate to counter-act the virus. Reports have shown that the bNAbs have been purified and are now used in passive vaccine, although it still is not as effective as researchers would hope. The problem is that they do not know the pathways of bNAbs enough to understand how they work. As previously stated, more research is needed to be able to find a way to use them in vaccines or as a way to understand how the immune system can work against the virus.
ReplyDeleteIt appears that several experimental trials are being tested on animals and humans to find an effective cure for AIDS. In 2009, researchers published findings from an HIV vaccine trial in Thailand. That trial involved more than 16,000 adults and showed that a combination vaccine was safe and lowered the rate of HIV infection by 31.2%. Scientists are now trying to take what they learned from the Thai trial and make a better vaccine with greater and more definite effectiveness.
ReplyDeleteScientists have been studying dozens of potent antibodies that can neutralize the HIV virus. Progress is being made and a lot of information is being uncovered through these experimental trials. I believe that one day we will discover a vaccine for AIDS. Some may call it hopeful, I call it optimistic.
- JLo