The field of HIV prevention has its share of raging controversies, but there's one thing almost everyone agrees on -- an effective HIV vaccine is desperately needed. After an embarrassing burst of optimism for a failed first-generation product in the early 1990s, vaccine research has been widely perceived as stagnant. But in the past year or so, promising new research is starting to rekindle hopes that an HIV vaccine is possible.
The way the next generation vaccines may work, however, is still considered less than perfect by some researchers. An ideal vaccine would be one that prevents HIV from ever establishing itself in the body. Known as "sterilizing immunity," such a vaccine would leave an individual free from HIV after an exposure. With our current technology, that may be very difficult to achieve. This has led researchers to concentrate on developing vaccines that, if unable to prevent infection, may at least prevent the virus from subsequently causing illness. Several vaccine candidates attempting this approach are now entering human trials, and the scientists involved are cautiously optimistic that their studies may prove successful. But questions remain about what counts as "success." If a vaccine allows HIV to enter the body but then controls it, is there a chance that the virus could be reactivated later in life and cause disease? Might regular booster vaccinations be required to maintain control? Only long-term studies can provide answers, and with infection rates in some countries poised to explode, there is the compelling argument that, for those at risk, some protection against AIDS is better than none at all.
To grasp the science behind these issues, it's necessary to delve into the complex workings of the immune system. Over the past decade, AIDS research has helped revolutionize our understanding of how the immune system fights infection and has opened new windows onto how vaccines really work.
The key concept behind vaccination is immune system memory. The famous experiments of Edward Jenner uncovered this aspect of immunity in the late 1700s. Jenner noticed that women and girls who milked cows regularly seemed resistant to the scourge of smallpox, and he guessed the reason might be connected with their exposure to cowpox, a very similar disease that struck cattle. In an experiment that would be considered far from ethical today, Jenner made a preparation from cowpox lesions and gave it to a young boy to inhale. Despite subsequent exposures to smallpox, the boy avoided disease.
Remarkably, it has taken over two centuries to begin to understand exactly why Jenner's guesswork paid off. The technical challenges involved in studying the immune system have, until recently, obscured many details of how the body "remembers" past infections in order to protect against future exposures. Even more relevant to HIV/AIDS, the way the body controls infectious agents that stay in the body for life -- like hepatitis B or TB, for example -- has also been a mystery.
The immune system is like a complex army of cells that perform many different functions in the battle to maintain health. The first line of defense against infection is called innate immunity. This refers to cells such as neutrophils and natural killer (NK) cells that respond to infections in a general way without specifically recognizing or "remembering" the infectious agent responsible. The more important aspect of immune function when it comes to vaccines and most serious illnesses is called adaptive immunity. Members of the adaptive immune system -- T-cells and B-cells -- actually target specific infectious agents and then afterwards provide the body with a "memory" of these particular bugs.
T-cells and B-cells both belong to a class of cells called lymphocytes. The job of B-cells is to make antibodies. Antibodies are like flags that stick to infectious agents as they float freely in the bloodstream, thus marking them for destruction and elimination from the body. The production of antibodies is key for protection against certain kinds of infections, such as those caused by bacteria. However, for viruses like herpes and HIV, which actually insert themselves into the body's cells (the technical term for these nasties is "intracellular pathogens"), antibodies don't work as well. To control this type of inside-the-cell infection, it appears that the body depends on its T-cells.
Our understanding of the role of T-cells in immunity has progressed by leaps and bounds over the past few years. For this we must thank the involuntary altruism of thousands of mice, which have been specifically bred for the study of the T-cell immune system. Technological approaches to analyzing T-cell function have also improved. New insights into how T-cells work have provided the basis for many of the latest HIV vaccines and proposed immune-based treatments for HIV infection. The next section of this article attempts to summarize our new understanding of T-cells and their functions.
There are two important families of T-cells in the body, and markers on the cell's surface can identify them. T-cells with a marker called CD4 belong to a family known as T-helper cells. T-helper cells fulfill the commander's role in the immune response, delivering signals to other immune system cells that allow them to carry out their functions. CD8 markers are found on another important family of T-cells called cytotoxic T-lymphocytes or CTLs for short. "Cytotoxic" means that they can kill cells in the body that have been infected with a virus or another pathogen -- for this reason CTLs are also known as killer T-cells.
T-cells start life in the cell-making factories buried within our bones. From there the immature or "progenitor" T-cells travel to a small organ located just behind the breastbone called the thymus. The thymus acts a boot camp for T-cells, and only cells that graduate are allowed to enter the body's circulation as new recruits to the immune system army.
Several important events occur in the thymus. It's there that a T-cell acquires the CD4 or CD8 marker that signals the cell's function. Both CD4 and CD8 T-cells also develop a structure called a T-cell receptor (TCR). The TCR is a docking bay for pieces of infectious agents, like viruses and bacteria that have been picked up by one of the body's scavenger cells. The TCR has to recognize not only the infectious agent, but also a protein called MHC that identifies the scavenger cell as trustworthy. The MHC is like a secret handshake the T-cell needs to receive before it can act. If the T-cell's TCR locks snugly onto a piece of an infectious agent combined with an MHC protein, an immune response can be triggered. Any piece of infectious agent that can fit into a TCR and trigger an immune response is called an antigen. It is the TCR that allows an immune response to be directed against a specific pathogen. New TCRs are produced and individualized in the thymus by an essentially random shuffling of the T-cell's genetic code, or DNA. Billions of T-cells with many differently shaped TCR docking bays are made in this way. This seems to be the body's method of making sure that for any potential pathogen, there will be at least some T-cells able to recognize its antigens.
There's a downside to this process. T-cells are also made with TCRs able to dock with pieces of one's own body tissues, or self-antigen. If these anti-self cells leave the thymus and enter the circulation, there can be an immune response against the very body that the T-cells are supposed to protect. This problem is called autoimmunity. So the final task for the thymus is to eliminate T-cells with TCRs that might cause autoimmune responses. In fact, 95 percent of newly made T-cells are destroyed in the thymus for this very reason. Members of the remaining 5 percent graduate from T-cell boot camp, enter the circulation and start patrolling for antigen to fit their TCR and trigger a T-cell response.
These fresh T-cells are called naive, because they have not yet responded to an infection. They can be thought of as the rookie T-cells of the immune system. If a new infection (or fake infection in the form of a vaccine) shows up, naive T-cells with TCRs that can dock with pieces of the infectious agent will be the ones recruited to respond. This first encounter of naive T-cells with a new infection is called the primary immune response.
An average adult is estimated to have one to two trillion naive T-cells on patrol at any given time. New naive T-cells are made and graduate from the thymus every day, replacing an equivalent number of naive cells that never found an infection to respond to. Scientists estimate that the body makes about one to four billion new naive T-cells a day during adulthood, though this number declines dramatically as individuals age.
The events set into motion when a naïve T-cell docks with antigen fitting its TCR are key to understanding immunity. To walk through what scientists think occurs, it's helpful to look at the immune response to a viral infection most everyone has experienced: Chickenpox.
Chickenpox is caused by an easily transmitted virus called herpes zoster virus (HZV). Most people become infected with HZV during childhood. When the virus first arrives in the body, immune sentries chop it up and its pieces are transported to the lymph nodes by immune system foot soldiers called dendritic cells. The lymph nodes are immune system command centers and T-cells visit them regularly, eager to mix it up with infectious agents. When a dendritic cell carrying HZV fragments arrives at the lymph node, it displays pieces of the virus for passing T-cells to inspect. This is called antigen presentation. Any naïve T-cell with a TCR that docks snugly to HZV antigen will be embraced by the dendritic cell. This removes the T-cell from patrol and starts the immune response process against HZV.
The T-cell/dendritic cell embrace lasts several days, during which time signals are exchanged that cause the T-cell to prepare for battle. Eventually, the T-cell becomes activated, which means that it starts to make copies of itself. And each copy made starts to make copies of itself, also. Since a single naïve T-cell can make twenty or more copies of itself, this multiplication process generates a cascade of millions of T-cell clones that all have the same kind of TCR, in this case TCRs that specifically dock with HZV antigen.
This army of activated, HZV-specific T-cells leaves the lymph nodes on a search-and-destroy mission. Their task is to find and eliminate HZV-infected cells and limit the ability of the virus to reproduce. To perform this mission, activated T-cells also develop enhanced infection-fighting skills. They release chemicals called cytokines and chemokines that can communicate with other cells and, in some cases, directly block viral replication. CD8 killer T-cells release chemical weapons such as "perforin" that punch holes in virus-infected cells.
Most people can remember what it felt like when the war between the immune system and HZV was raging. Fever, swollen lymph nodes and blistering skin are the unforgettable hallmarks of chickenpox. As you might guess, many of these symptoms stem from the activity of the HZV-fighting T-cells themselves. Swollen lymph nodes result from the proliferation of naïve T-cells when they become activated. Fever is partly a result of the cytokines and chemokines that the T-cells release (one of the best known cytokines is called IL-2, and when used as a treatment, IL-2 is notorious for causing fever and flu-like symptoms).
Fortunately, after a week or so of this misery, the T-cells have usually gained the upper hand. HZV replication is controlled, and most of the newly made, activated T-cells automatically die off. The symptoms of chickenpox subside. What has been long suspected, but only recently proven, is that some of the HZV-specific T-cells survive. Out of the twenty or so duplicates made by each naïve T-cell activated by the virus, it seems that two to five cells become memory T-cells. These memory T-cells can be thought of as a SWAT team the body retains to deal with HZV should it ever try to cause trouble again. HZV, like hepatitis B and tuberculosis, is an example of an infectious agent that remains in the body for life.
Recent studies have helped show how memory T-cells prevent infections from recurring. Remember the lingering embrace between the antigen-presenting dendritic cell and the naïve T-cell? A memory T-cell can become activated and get into battle after a much shorter embrace -- the immune system equivalent of a hug, perhaps. Memory T-cells also seem to be able to copy themselves more rapidly, and they start releasing cytokines, chemokines, and other infection-fighting chemicals almost instantly (See Genes Are Go below).
As you may have already realized, it's the difference between naïve and memory T-cell response rates that were responsible for the success of Edward Jenner's experiment and all the vaccines that came after. The dried cowpox used by Jenner to vaccinate the young boy was presented to naïve T-cells, and those cells with TCRs fitting the cowpox antigens responded and left a legacy of cowpox-specific memory T-cells. The similarities between cowpox and smallpox antigens meant that this SWAT team of T-cells was able to respond rapidly when the boy was later exposed to smallpox. And most importantly, thanks to this rapid response, deadly disease was averted.
In addition to two trillion or so naïve T-cells, an adult usually has a pool of around three trillion memory T-cells. This pool contains memory T-cells produced in response to past infections, and in some ways can be thought of as a library containing a body's history with infectious disease. AIDS is a horrific illustration of the importance of these memory T-cells -- the opportunistic infections that are the hallmark of AIDS are all caused by pathogens that stay in our bodies for life. When the memory T-cell squads that control these infections are diminished in number by HIV infection, pathogens such as pneumocystis, candida, cytomegalovirus, and toxoplasma can become active and cause disease.
It is here in the T-cell story that we must climb to another level of complexity. For the sake of clarity -- never easy to achieve when discussing the immune system -- the above discussion of chickenpox talked about T-cells in a general way. But as already mentioned, the CD4 and CD8 markers identify two important groups of T-cells -- helpers and killers -- with very different functions. Although the process (described above) that leads to the creation of memory T-cells is similar for both CD4 and CD8 T-cells, the ways antigens are presented to CD4 and CD8 cells are somewhat different. This is important since researchers would like a vaccine that creates a squad of both CD4 and CD8 memory T-cells.
CD4 helper T-cells seem to divide into two major groups. Type 1 (called Th1) CD4 T-cells provide important help to CD8 killer T-cells. Type 2 (called Th2) CD4 T-cells help B-cells make antibodies. Again, these distinctions become critical when designing vaccines. Researchers are now trying to work out what type of memory T-cell squad is more important for protecting against a particular infection. If antibodies are important, then a vaccine had better trigger the development of Th2 CD4 memory T-cells that will respond rapidly to provide help for B-cells. If a pathogen manages to penetrate cells in the body and CD8 killer T-cells are needed to eliminate or control it, then a squad of Th1 CD4 memory T-cells has to be created to help get those killer cells going. For some infections -- including HIV -- it may be best to trigger both Th1 CD4 and CD8 killer memory T-cells. That way, the whole team will be ready to roll.
It's important to stress that one type of T-cell response does not mean the other type can't respond simultaneously. However, the relative strength of the different types of T-cell response appears to be important for determining whether an infection is successfully battled. Looking back at the example of HZV, it's likely that all of these different T-cell players get involved in the battle -- both Th1 and Th2 CD4 T-cells, CD8 killer T-cells, B-cells, and antibodies.
Based on experience with other viruses, many researchers suspect that it's the teamwork between Th1 CD4 and CD8 killer T-cells that plays the most important role in controlling HZV over the long haul. These suspicions are supported by research in animals with similar viruses that stay in the body for life but remain controlled by memory T-cells. Conversely, with other infections the strength of the Th2 CD4 T-cell response and the production of effective antibodies by B-cells seems key.
You may be wondering what types of immune responses were created by your childhood vaccinations. Philip Kourilsky, a researcher from the Pasteur Institute in France, has recently highlighted the fact that for almost all commercially available vaccines (such as hepatitis B, measles, polio, etc.) what makes them effective -- and which T-cell responses they create -- is not known. "We've had many successful vaccines over the past decades but we've missed a chance to see how these vaccines work," Kourilsky said at a recent HIV vaccine meeting. Up until recently the assumption had been that antibodies were responsible for the success of vaccines, but it is now thought that this isn't the case, a point stressed at the same meeting by Neal Nathanson, former director of the U.S. Office of AIDS Research. "Hepatitis B vaccine is a good example. It's amazingly effective but no one knows how it works. And what's really interesting is that it does work, even though hepatitis B is a persistent infection -- like HIV." Supporting Nathanson's interest is a study that compared people who controlled hepatitis B infection naturally with those who had been vaccinated. In that study, natural immunity seemed to rely on Th1 CD4 T-cell responses, not the Th2 responses that are associated with antibody production.
While scientists may never get around to analyzing how older vaccines do their job, HIV researchers are benefiting greatly from the latest advances in T-cell research. Several vaccine candidates that are specifically designed to create Th1 CD4 and CD8 killer memory T-cell responses against HIV are now entering clinical trials for the first time.
Attempts to create CD8 killer T-cell responses have been assisted by the development of a vaccine technology called "naked DNA." This strategy uses sections of DNA that contain genes for making fake HIV proteins that can act as antigens to trigger an immune response. Because these fake antigens have the same structure as real HIV antigens, naïve T-cells are embraced and memory T-cells specific for HIV antigen are created. One downside is that the dendritic cells needed to present these antigens to T-cells are not very impressed by the fakery involved. As a result, the memory T-cell response to naked DNA vaccination alone is rather weak.
Researchers have addressed this problem by following naked DNA vaccination with a booster shot. The booster shot uses harmless bird viruses that have also been tinkered with so that they too produce fake HIV antigens. The booster bird virus does a better job of fooling the antigen-presenting cells than plain DNA, thus causing a massively enhanced T-cell response.
One of the first inklings of the potential success of this strategy came in an article published in 1998 by a group of Australian researchers led by Dr. Stephen Kent. Kent's team tried a naked DNA shot followed by a bird virus (called fowlpox) booster in macaque monkeys. Strong Th1 CD4 memory T-cell and CD8 memory T-cell responses were created by the vaccine regimen. They later injected real HIV into the monkeys and found that, after a short burst of viral replication, the memory T-cells kicked in and reduced HIV activity to undetectable levels. However, the type of monkey used in that experiment doesn't progress to AIDS or develop high levels of HIV replication -- even without vaccination. While it was a good first step, more studies were needed.
A year later Dr. Harriet Robinson, a former colleague of Kent's, published similarly promising results obtained with her own version of what's being called the "prime-boost strategy." Robinson actually feels she may have bested Kent's efforts by using a method for delivering the naked DNA under the skin (intradermally). Robinson also challenged her vaccinated monkeys with a potentially lethal form of monkey HIV called SHIV. After publishing her results Robinson pointed out that "protection did not prevent infection -- what we saw were contained infections." Although SHIV took root, virus could not be detected using viral load tests, showing that the memory T-cell response had squelched SHIV replication very effectively.
In both the Kent and Robinson studies, it was notable that antibody responses to the vaccines were variable and often not detectable. The researchers concluded that the Th1 CD4 and CD8 killer T-cell response generated by these vaccines was able to control virus activity in the absence of antibody. This observation truly heralds a new era for vaccine research, which for so long has been hamstrung by the notion that antibodies are central to all types of protective immunity.
Equipped with a better understanding of the immune responses required to control HIV, several companies and research teams are moving their vaccine candidates into human trials.
Stephen Kent's vaccine has now been named Co-X-Gene. The manufacturer is a small Australian company called Virax with limited resources, leading to some concerns about their ability to move the product forward. As this article went to press, Virax announced they have entered into partnership with Aventis Pasteur, a huge French vaccine manufacturer that produces a billion doses of commercial vaccines a year. Flush with this injection of support, Virax plans clinical trials of Co-X-Gene during 2001, with larger trials possible within three years.
Merck & Co., the pharmaceutical giant, has also been quietly working away on a T-cell based HIV vaccine. Merck is also using a naked DNA and fowlpox booster strategy, although researchers there claim to have modified the DNA so that it generates HIV antigens more efficiently. Merck surprised everyone by announcing the first human safety study of this product last year. The government's assistant director of AIDS vaccine research, Margaret Johnston, waxed enthusiastic in the Wall Street Journal: "It's good to see Merck involved, and testing an approach that is right now thought to be on the cutting edge." The trial is already under way, with one of the participating sites being the State University of New York at Stony Brook. Potential volunteers can call Michael Thorn, RN, at (516) 444-1659 for more information.
Another DNA vaccine made by Apollon, Inc. is also in human trials. Currently, the product does not feature a bird virus booster but could potentially be modified if studies support such a move. Temporarily laboring under the rather forgettable name of APL-400-03, the vaccine is under study at the National Institutes of Health [contact: Grace Kelly, 1-800-772-5464, extension 57744, and the University of Pennsylvania, contact: Kim Lacy at (215) 662-6434].
Further afield, a collaboration between English and Kenyan researchers plans safety testing of a DNA vaccine with a booster made from a type of virus called vaccinia (the full name is modified vaccinia Ankara, or MVA). The initial studies will be in the UK with further work scheduled in Nairobi, Kenya.
In Uganda, plans are under way to test the first-ever oral HIV vaccine candidate. The brainchild of researchers at Robert Gallo's Institute of Human Virology in Baltimore, this novel approach uses genetically modified salmonella bacteria to produce HIV antigens in the gut. Because most HIV transmission occurs through vaginal or anal mucosal surfaces, stimulating a strong T-cell response in these kinds of tissues could be particularly useful. The always cautious Dr. Tony Fauci, head of the U.S. National Institute of Allergies and Infectious Diseases (NIAID), recently relayed a cheekily guarded optimism about the product to the journal Nature: "We have been burned before in trying to predict how a candidate will fare before the trial even starts. Having said that, I like this approach."
While this is a sampling of the newer vaccines furthest along in development, the scent of potential success may soon prompt more products into the field. In anticipation, NIAID recently announced a revamping of their HIV Vaccine Trials Network (HVTN), expanding it to include sites in sub-Saharan Africa, Asia, Latin America, and the Caribbean. Significantly, the effort is being led by veteran T-cell immunologist Lawrence Corey, M.D., from the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle. Hopefully, the HVTN will be able to conduct the type of follow-up necessary to answer questions about the long-term efficacy of T-cell based vaccines and the ultimate outcome of an HIV infection that is controlled rather than evicted from the body.
Having crossed the cusp of a new millennium, there is a sense that HIV vaccine research has also reached a turning point. Not only is there optimism that the immune system can be prepared to do battle with this wily virus, but several promising new strategies may eventually prove able to block HIV's ability to create a home for itself in the human body. One thing is certain: The clouds of despair that dimmed the vaccine horizon are beginning to clear.
Although vaccine approaches focusing on T-cells have come to the fore, researchers have not entirely given up on antibodies. The difficulty has been triggering the body to produce antibodies that actually block HIV replication. HIV's outer envelope is notorious for mutating rapidly to avoid the antibody attack, and some scientists speculate that this is part of the virus's defense against the immune system. With some smart thinking, two teams of researchers believe they may be starting to surmount this problem.
Jack Nunberg from the University of Montana has worked out a way to generate antibodies that block HIV as it prepares to gain entry into T-cells. This first step of the entry process is called fusion, and Nunberg has dubbed his souped-up antibodies "fusion-competent." The clever idea that led to creation of these antibodies was to literally freeze HIV just as it was changing shape to fuse with a T-cell. The immune systems of mice were then used to make antibodies to these previously hidden parts of the virus. Isolated in the test tube, these antibodies were able to block replication of a wide variety of HIV strains collected from around the world. There is much more work to be done before this strategy can be tried in humans, but Nunberg remains cautiously optimistic that his research will eventually bear fruit.
At the National Cancer Institute in Maryland, Dr. John Schiller is trying another cleverly designed antibody-based approach. It was discovered several years ago that HIV uses two T-cell surface molecules when latching onto and invading a cell. One latch has long been known to be the CD4 molecule itself, which is vital to helper T-cell function. Early attempts to block the CD4 latch failed spectacularly. The second latch HIV needs is a receptor called CCR5, the function of which -- if any -- is not known. What is known is that some people naturally lack CCR5 receptors on their T-cells due to a genetic mutation. Not only are these people highly resistant to HIV infection, but as far as anyone can tell they are perfectly healthy. These observations have prompted several drug companies to design drugs that block CCR5, betting that they might become effective treatments for HIV.
Dr. Schiller had another idea -- why not try to get the body to make antibodies that block CCR5? This approach has a number of advantages: a vaccine that created antibodies against CCR5 just might offer the kind of long-term protection against HIV infection seen in people naturally lacking the CCR5 receptor. And as a treatment, a shot or two of a vaccine would be immensely preferable to the daily ingestion of a drug. Schiller has reported success with the approach in mice and is moving on to macaque monkeys. "If we can do it in macaques, then the chances that it won't work in humans are small," says Schiller. If either Nunberg or Schiller hit the jackpot, antibodies will be back in the HIV business.
Lest we forget, there are HIV vaccines further along in human trials than those discussed in the body of this article. Unfortunately, they were developed prior to the recent significant insights into T-cell immunity. AIDSVAX is a vaccine that uses a fake copy of HIV's outer envelope to try to stimulate antibodies against the virus. Many researchers now feel that this product may have a limited protective effect, if any. This dour outlook emerged as several breakthrough HIV infections occurred during early AIDSVAX trials. Pasteur Merieux Connaught's ALVAC vaccine attempts to induce both antibodies and T-cell responses by combining pieces of HIV's envelope with a bird virus booster. The results so far have been disappointing, with killer T-cells being detected in only one-third of study participants. UK killer T-cell expert Dr. Andrew McMichael, when asked his opinion by the journal Science, was underwhelmed: "Two-thirds of the people (had) no killer T-cell response, and, if killer T-cells are important, they wouldn't be protected."
Two additional details are critical to the design of an effective HIV vaccine. Naked DNA, bird viruses, and a variety of other strategies can be used to deliver fake HIV antigens (pieces of HIV that can trigger an immune response) into the body. But which pieces of HIV should be used? Early vaccine research focused on HIV's outer envelope, but it has become apparent that the rapid mutation of this viral cloak may be part of its defense against the immune system. It also seems that HIV's envelope proteins create antibody responses, not the Th1 CD4 and CD8 killer T-cell activity now thought to be vital for a successful vaccine. Researchers are now targeting certain inner proteins of HIV called core proteins that are revealed only after the virus has infected a T-cell. The genes that make these core proteins have catchy names like gag, pol, nef, and tat. In some cases single proteins may be able to induce T-cell immune responses. Italian researcher Barbara Ensoli has tried a vaccine that uses HIV's tat protein, and this approach was sufficient to protect two thirds of her vaccinated cynomolgus monkeys from active HIV replication. Ensoli acknowledges, however, that single protein approaches can probably be improved upon if combined with other vaccines. The most important lesson from recent vaccine studies is that HIV's core proteins create much stronger Th1 CD4 and CD8 killer T-cell responses than the ever-changing viral envelope. Whether particular core proteins have unique advantages when it comes to vaccination is not yet known. Because a T-cell with a TCR that fits an HIV gag protein won't respond to tat, it may be better to include as many core proteins as possible, thereby maximizing the number of T-cells that respond to the vaccine.
Adjuvants are special vaccine ingredients designed to boost what researchers call "immunogenicity." Simply shooting a fake HIV protein into the body does not necessarily ensure that dendritic cells will be inclined to pick it up, take it to the lymph nodes, and present it to T-cells the way they would with a real virus. An adjuvant is designed to help fool the antigen-presenting dendritic cells into treating the vaccine like the real thing. Many older vaccines use adjuvants made up of bits of dead bacteria suspended in an emulsion of oil and soap that helps mobilize a larger immune response. Naked DNA vaccines can contain bits of bacteria-like DNA called CpG motifs, and these also appear to have adjuvant effects (although, there are some yet-to-be researched questions about the safety of these CpG adjuvants). Bird virus boosters seem to trigger the body to produce cytokines that help spark antigen presentation, which is another reason they have become favorites in HIV vaccine studies. Research into adjuvants continues, with a recent study actually using a patient's own dendritic cells to carry vaccine antigens into the lymph nodes. A single shot of dendritic cells generated a huge T-cell response. Unfortunately, harvesting, then re-infusing dendritic cells is costly and it's unclear whether this approach can be made affordable enough for widespread use.
The reason memory T-cells outperform naive T-cells when responding to infections is related to the activity of genes within the cell. Genes are short stretches of DNA that contain code for making certain proteins. The proteins then perform specific functions in the body. Most of us are familiar with the idea that we inherit genes from our parents for things like eye color. It's often less appreciated that our genes are at work every second that we are alive. Every cell in our body (apart from red blood cells) contains a complete copy of our DNA blueprint (called the genome) and all our genes are contained within it. However, cells only use the genes they need to function. A T-cell uses certain genes to make the proteins it needs to fight infection. A kidney cell will use different genes to perform the waste-eliminating functions of the kidney. One way to think about this is that each cell carries a complete library containing the thousands of instruction manuals needed for making an entire body. But each cell checks out only those volumes needed to carry out its specific functions.
An illustrated pamphlet, Understanding the Immune System, is available from the National Institutes of Health (NIH) Web site: http://www.niaid.nih.gov/publications.
For more on vaccines, Understanding Vaccines http://www.niaid.nih.gov/publications/vaccine/undvacc.htm