Tag Archives: vaccine

Does the Flu Vaccine Work?

There is a photo circulating on Facebook that shows the package insert for a flu vaccine that appears to indicate that the vaccine has not been shown to be effective against influenza. Of course, this has gone viral, (sorry for the pun) especially among the anti-vax crowd.

I wanted to do a little investigating to understand the statement on the package insert. The insert says: “FLULAVAL is a vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine… This indication is based on immune response elicited by FLULAVAL, and there have been no controlled trials adequately demonstrating a decrease in influenza disease after vaccination with FLULAVAL”

Its the last statement that has triggered concern: no controlled trials adequately demonstrate a decrease of influenza disease after vaccination? Sounds bad, so lets take a look. The package insert actually has 14 pages. They show the results from a 2005-2006 clinical study involving 7482 people. About half received the vaccine and half received a placebo. Then they followed those individuals to see who got the flu. 23 people receiving the vaccine got a strain of flu against which the vaccine is supposed to protect. 45 receiving the placebo got those same strains of the flu. The statistical analysis shows a vaccine efficacy of about 46%, but the calculation of the confidence interval suggests the efficacy could be as low as 9.8%. Before doing the clinical study, they decided that the lowest limit of the confidence interval had to be above 35% to be considered successful. So it seems that the statement that clinical trials have failed to show efficacy is correct due to the large error range in their data.

Lets consider the other statement, that FLULAVAL is indicated based on it eliciting an immune response. Data from another study is shown in which people were given the vaccine and after 2 weeks, then checked for production of antibodies. In this study the levels of antibody increased to high enough levels in enough individuals that the vaccine met the criteria for success. Furthermore, they did a test called an Immunological Non-Inferiority test. Basically, they wanted to know if FLULAVAL induces an antibody response that is at least as good (ie not inferior to) another vaccine available on the market, FLUZONE. FLULAVAL induced as good a response as FLUZONE. (If you take a look at the FLUZONE package insert, they only report data on antibody responses, and state that no data is available on whether FLUZONE reduces incidence of influenza).

So there appears to be something of a conflict: the clinical trial was not successful but the vaccine appears to induce an appropriate response. Perhaps the measurement of antibodies is not the ideal indicator for predicting protection? This speaks to an important question in vaccine development, which is determining the correlates of protection. That is, what specific part of the immune response is needed for immunity?

Lets also look at other flu vaccines. FLULAVAL is one of seven different flu vaccines available.
Fluarix: Clinical studies show a reduction in influenza disease in vaccinated vs placebo groups.
FluMist: Clinical studies show a reduction in influenza disease in vaccinated vs placebo groups. The data for FluMist are the most impressive, getting as high as 96% efficacy with certain flu strains.
FluVirin: Only shows immunogenicity data, induces antibody response that exceeds the threshold defined for success.
FLUZONE: Only shows immunogenicity data, induces antibody response that exceeds the threshold defined for success.
Afluria: Only shows immunogenicity data, induces antibody response that exceeds the threshold defined for success.
Agriflu: Clinical studies show a reduction in influenza disease in vaccinated vs placebo groups.

Interestingly, it appears that approval of flu vaccines is based on showing that the vaccine can induce a strong antibody response, not showing that the vaccine prevents the disease.

Package inserts don’t communicate the whole story. We also have to consider the total body of evidence, not just one or two tests. There are many other clinical trials demonstrating the efficacy of flu vaccines. Such as this one, this one, this one, and this one.
In the clinical trials described in the package inserts, the severity of disease is not indicated. Did the vaccinated people get less severe disease than the non-vaccinated people? A vaccine that induces sufficient immunity so that it prevents severe disease although you might still get a sniffle, would still be pretty good. There are other outcomes to consider too. Does the vaccine reduce transmission or complications following influenza disease? In Canada, Ontario made efforts to dramatically increase influenza vaccination, with the result of reduced influenza associated mortality and reduced healthcare use. And take this study in which it was found that vaccination of healthcare workers didn’t reduce incidence of flu in those vaccinated but reduced the mortality rate of their patients.

There is an obvious need for a flu vaccine that induces better protection, especially in children and the elderly, and ideally, one that is universal so we dont have to go every year to get a shot and dont have to depend on predictions of what is going to circulate in the future. But the evidence that the flu vaccine is beneficial for individuals and society is pretty strong. Finally, I think this emphasizes the importance of digging deeper to understand the information around us. It is never as simple as it seems and we must avoid reducing information to the simplest single sentence thus removing the underlying complexities.

Disclaimer: I am “not that kind of doctor” so this is not intended to provide any medical advice or recommendations for which vaccine to use.


Goodbye Rinderpest, Hello Measles

Variola virus, the agent of smallpox, once held a lonely spot on the list of globally eradicated diseases. Now it is joined by rinderpest, the cattle plague. The OIE (Organization for Animal Health) declared the disease eradicated and the UN’s Food and Agriculture Organization (FAO) is expected to adopt a resolution in June declaring it eradicated. The disease affects cloven-hoofed animals and can have an extremely high mortality rate in some cattle and buffalo. It is also extremely contagious, so its rapid spread through livestock can have an obviously large impact on animal health, food production and livelihood of cattle farmers. Thanks to an intensive word-wide vaccination effort, rinderpest virus can now be added to the list of organisms we actually intended to make extinct.

Rinderpest is caused by rinderpest virus, a member of the Morbillivirus genus. Another member of that genus is measles virus. Oh, and there is a vaccine for that too. In fact North America was free of measles in 2002 and perhaps it was on track for global eradication. But not anymore.

My son recently turned one, so I took him to get his measles, mumps and rubella (MMR) vaccine, feeling confident that Im helping protect him from three pretty nasty viruses, and not giving him Autism. In fact, before he turned one, I’d been feeling a little anxious about getting him the vaccine soon enough. My email inbox keeps filling up with notices from ProMED mail (Program to Monitor Emerging Diseases) with news of various measles outbreaks across the globe.

There are outbreaks all over Europe, especially in France, the UK, Spain and Switzerland. The epidemic in France that started in 2008 has now reached over 14,000 people, with 9000 of those infections reported in the last 6 months. (France has a vaccination rate of about 60%. Vaccination rates in the UK bottomed out at 80% and are slowly on the rise again). Outbreaks in the USA and Canada have been small, the vaccination rates are higher but not high enough. Many of these can be tracked to travel of unvaccinated individuals to areas where measles is still endemic or flaring up. In Minnesota, an outbreak counting 21 people has sent 13 people to the hospital (an unusually high number). Of the 21 people, 8 were old enough to be vaccinated but weren’t, 7 were too young to be vaccinated, 1 was vaccinated and the status of the others is unknown.

The Minnesota outbreak emphasizes an important point: it is necessary to maintain a sufficiently high level of herd immunity to prevent outbreaks and protect those who can’t be vaccinated. For most diseases, vaccination rates need to be at or above 95% to prevent outbreaks, and may need to be even higher for measles. Virus transmission depends on the virus finding a susceptible host. If a population is primarily made up of immune individuals, the virus has a hard time maintaining a chain of transmission.

Vaccination is therefore not just a matter of personal health, but community health. Maintaining high herd immunity helps protect babies too young to be vaccinated by limiting the chances that they ever encounter the virus. Don’t just get your kids vaccinated to protect themselves, do it to protect us all.


Swine Flu: New and Improved!

Contributed by guest blogger: Marni Hershbain ’11

Flu season is never enjoyable, but some seasons are certainly worse than others. The 2009 swine flu outbreak was particularly serious because the 2009 H1N1 strain was a novel virus, formed via the reassortment of swine, avian and human flu viruses. There were over 600,000 confirmed cases of H1N1 and over 18,449 deaths during the course of the pandemic. While this sounds pretty bad, it could have been much worse. The transmission efficiency of H1N1 was actually much lower than those of other pandemic strains, such as the 1918 H1N1 strain. Unfortunately, recent research demonstrates that this could change.

Flu strains are characterized by the hemagglutinin and neuraminidase found on their surfaces, hence names like H1N1. In order for the virus to infect a cell, hemagglutinin on the surface of the virus must bind to glycan receptors on the cell. Therefore, to explain the low transmission efficiency of 2009 H1N1, researchers looked to its hemagglutinin.
In most flu strains, the amino acids at positions 219 and 227 within the hemagglutinin are both hydrophobic or both charged. In 1918 H1N1 both are hydrophobic. However, the 2009 H1N1 strain has isolucine, a hydrophobic molecule, in position 219 and glutamic acid, a charged molecule, in position 227. Researchers hypothesized that lacking either hydrophobic or ionic interactions at these positions would disrupt the positioning of neighboring residues and decrease the hemagglutinin’s binding affinity. They further hypothesized that if they replaced isolucine with the charged amino acid lysine, stable inter-residue interactions would occur and binding affinity would increase.

When researchers compared the ability of wild type and isolucine→lysine mutant strains to bind to an array of glycans representing human binding sites, they found the binding ability of the mutant strain was 30 times greater. The mutant version also bound more intensely to receptors in human tracheal tissue. Researchers also infected ferrets (commonly used as models in human influenza studies) with either wild type or mutant virus. Only the ferrets infected with mutant virus spread the infection to all of the previously uninfected ferrets placed in close proximity to them.

The mutation of just one amino acid could greatly impact the transmission efficiency of 2009 H1N1. Flu viruses tend to mutate frequently, which is why a new vaccine needs to be developed every year. Predicting what these mutations will be is not an easy task, but mutations at the positions in this study will certainly be monitored closely.


A possible new HIV vaccine target?

Contributed by guest blogger: Lydia Mendoza ’11

In 2009, it was estimated that 33.3 million people in the world were living with HIV/AIDS. Since the discovery of HIV, more than two decades ago, money has poured into research in the hopes that an effective vaccine might be developed. As of yet a vaccine remains elusive. One reason why it is so difficult to create a vaccine is because HIV is highly mutable and genetically diverse subtypes, or clades, have evolved. A vaccine needs to be able to offer protection from a range of HIV clades.

Normally viral vaccines are based upon neutralizing antibodies, which prevent infection of the host cell. The first attempts to develop neutralizing antibodies against HIV targeted gp120, which is known to play a role in HIV’s ability to enter and infect CD4 t-cells. These attempts have not been successful as of yet because of the gene’s high rate of mutations. However a recent paper has shown that the V3 loop of gp120 is a potential vaccine target.

The strand of protein known as the V3 loop was never thought to be an attractive vaccine target because it is not highly conserved. However, it appears to have conserved structural elements that are involved in interactions with coreceptors. To study whether V3 was a viable vaccine target, a human monoclonal antibody, HGN194 was used. HGN194 was isolated from memory B cells of a person infected with HIV-1 clade AG circulating recombianant form (CRF). HGN194 targets the V3 loop and has been previously shown to neutralize a broad range of neutralization-sensitive and resistant strains of HIV.

The study evaluated whether HGN194 was able to protect rhesus monkeys from an HIV model system. One group of monkeys was injected with HGN194 then they were challenged with a high dose of a clade C SHIV, which is a chimeric simian-human imunodeficiency virus encoding HIV envelope genes in a SIV backbone. The second group of monkeys was also given a high dose of SHIV but was not given the HGN194. The monkeys given the antibody were protected from SHIV infection, and those not given the antibody were infected. The researchers concluded that HGN194, isolated from an HIV-positive individual harboring a clade AG CFR, was able to confer complete cross-clade protection against clade C SHIV.

The antibody apparently latches onto the virus’s V3 loop and prevents the virus from invading cells. This does not mean that this antibody treatment technique is a vaccine for HIV. It does not create long-term protection because the antibodies do not remain active in the body for very long. This is only a first step. A vaccine target has been identified but now scientists must create an antigen that induces formation of an antibody similar in structure to HGN194. There is a lot of work left to be done but this finding hopefully brings researchers much closer to the development of a vaccine.


Can miRNAs help further attenuate influenza A vaccines?

Contributed by Guest Blogger: Brittany Sider ’11

MicroRNA (miRNA) molecules, first characterized in the early 1990s, have been implicated in a variety of different biological mechanisms. It took almost a decade for researchers to detect and understand the role of miRNAs in regulation of translation. Since then, research has focused on how we can scientifically manipulate these regulating molecules to our advantage in order to further understand biological underpinnings of certain diseases, as well as potential miRNA-based therapies.

The ability of the influenza virus to undergo frequent and substantial genomic mutations forces us to continually monitor its prevalence, and modify yearly vaccines to target the prevailing viral strains. Recently, live attenuated influenza vaccines (LAIVs, e.g. FluMist) have been proven effective, and have been distributed to a large portion of the eligible population to combat the seasonal flu. These vaccines are manipulated to become much more temperature-sensitive, and therefore are only capable of replicating in temperatures found in the nose. The inability of these attenuated viruses to replicate in the respiratory tract (due to higher temperatures) allows the vaccinated individual to produce antibodies to the influenza strains in the vaccine from the infection in the nasal passage. Therefore, the individual can produce the correct immune response without the virus spreading to the respiratory tract and causing symptoms.

In 2009, a group of researchers from Mount Sinai School of Medicine found that using microRNA response elements (MREs) can supplement the effectiveness of LAIVs. In the study, the MREs for the miR-124 (neural tissue-specific) and miR-93 (a ubiquitous miRNA) were inserted into open reading frames of influenza A nucleoprotein coding regions. The investigators vaccinated mice with miR-93-seeded strains, and then inoculated them with a lethal dose of influenza A/PR/8/34 H1N1 21 days later. This resulted in 100% survival of the subjects, as well as a robust immune response. In an attempt to attribute these results to other influenza strains, the same experiment was done with H5N1 (MREs were inserted into the vaccine specific for H5N1, and methods were repeated). Subjects who had received mock vaccinations 21 days prior to being inoculated with H5N1 displayed rapid weight loss, as well as 100% mortality. On the other hand, mice that had received the MRE-containing H5N1 strain did not display any signs of disease. Furthermore, serum from these subjects exhibited neutralizing activity against the wild-type H5N1, and a wide array of antibody responses (high levels of IgM, IgG1, IgG2a and IgG2b).

The results from this study lead the researchers to believe that MRE-containing LAIVs can be used, and potentially be even more effective than currently available LAIVs in protecting against influenza A outbreaks. In addition, this technology provides the potential to control for the degree of attenuation of the vaccine by manipulating the number of MREs/miRNAs. Lastly, FluMist – although proven to be equally as effective as injected vaccines – has some age exclusions. Perhaps the addition of MREs/miRNAs could expand the target demographic of this method of vaccination.


Eat Your Vaccines

Contributed by guest blogger: Nicole Engelhardt ’11

Usually when you get a vaccine it means you get a needle and a bandage. Not only that, but you get an attenuated virus. These weakened virus particles are strikingly similar to viable ones; they even infect cells. Because of their weakened state, they infect slower than natural virus particles, giving the body time to react. However, people who have weakened immune systems can still exhibit symptoms as if they were infected by the natural virus.

But a new tool may make this issue obsolete. What really matters when it comes to a vaccine is the shape of the particle, not the contents. The shape is recognized by B-cells in the body which then reproduce creating antibodies that attack all of the virus particles. However, these B-cells are very specific and very picky. Normally, it makes sense to use a weakened virus because it has the exact same shape as a normal virus and your B-cells will react to the vaccine as if it were the real thing. Is there any way, then, to produce the exact shape of the virus and therefore the correct antibodies without having the harmful side effects?

This paper explores the rotavirus particle which is the leading cause of gastroenteritis in the world. In some parts of the world, gastroenteritis can be deadly for many children. As it happens, the shape of the rotavirus particle can be mimicked almost exactly in plants. The shape of this virus is a capsid made out of proteins. First, the authors take the genes that code for the capsid proteins and insert it into the genome of the plants. Then the plants express the viral genes, creating the virus capsid proteins inside the cells of the plants. More incredible than that, these proteins self-assemble into the exact shape of the rotavirus capsid. Now you have a plant containing just the shell of the virus!

The experiments are still in their early stages, but when mice were fed these plants, the authors found they were producing the same antibodies that are produced when mice are actually infected with rotavirus. This bodes well for future research in humans. Once the antibodies are created, the severity of future infections is greatly decreased. If these transgenic plants do work, it could mean a safer and perhaps more affordable form of the vaccine that could help people the world over fight rotavirus before it can infect.


New Vaccine Protects Against Ebola Virus

Contributed by Guest Blogger: S. Goldberg ’14

Ebola Virus (EBOV) is a fairly new infection of the Filoviridae family, that causes Ebola Hemorrhagic Fever, or EHF. This infection can often be severe or fatal in humans and primates. Because it would be difficult to create a vaccine against all four different virus species of Ebola, scientists came up with a plan to develop a vaccine protective against a single species of the infection. An experiment was designed to test to see if a “prime-boost” strategy would work, with a vaccine protecting against one Ebola Virus species and protecting a different species at the same time. In the process of doing this experiment, it was found that the vaccine developed to protect primates against the two most lethal Ebola Virus species also protected against the newer Ebola virus species that was founded in 2007. The prime-boost vaccination provides immunity against newly emerging EBOV species and shows cross-protection against EBOV infection. In this strategy, the “prime” is a DNA vaccine that has a small amount of genetic material with surface proteins of the Zaire Ebola virus species and the Sudan Ebola virus, the two most lethal species of EBOV. The “boost” is made of a weak cold virus that delivers the Zaire EBOV surface protein. The experiment, conducted and overseen by the National Institute of Allergy and Infectious Diseases and the US Army Medical, gathered eight 3 to 5 year old cynomolgus monkeys as their test subjects, to see if such a vaccine actually protected against the two older Ebola virus species and the newer strain. Each of the monkeys were given the immunization and then transferred to a laboratory where they were exposed to the EBOV infection. The monkeys stayed their for the duration of the experiment. Using a blood analyzer, liver enzyme levels were examined on “days 0, 3, 6, 10, 14, 21 and 32”. During this test, samples of T-cell intracellular cytokines were taken. CD8+ T-cells were stained with antibodies, against intracellular cytokines. This technique allows for the frequency of antigen-specific T-cells to be determined. The production of cytokines plays an important role in the immune response of the body. After isolating the RNA of each subject, each of the monkeys given a vaccine that contained Zaire EBOV and Sudan EBOV glycoprotein (GP). After the GP was exposed within each of the bodies, the subjects developed “robust antigen-specific…immune responses against the GP from [Zaire EBOV] as well as cellular immunity against lethal…[Bundibugyo EBOV]”. After concluding this experiment, scientists have learned that current vaccines that can bring about T-cell immunity will have a greater possibility of “protecting against other [new] pathogenic EBOV species”.
If we have the ability to protect against new and emerging EBOV species, does that mean that, in the long-run, mutation of the virus will stop? Will existence of any EBOV species disappear? If it disappears, could it reappear? Could similar experiments be done to discover if a other currently used vaccines, aside those that display T-cell immune responses, are protecting against other unknown or new viral strains?


Millions of Viruses and Only One Drug

Contributed by Guest Blogger: M. Carraher ’14

A former leader of the Pentagon considers, “Mother Nature among the worst terrorists.” Throughout modern time, the threat of a virus pandemic has seemed more likely, and more deadly than a nuclear war. Swine flu, HIV, and SARS have all frightened average citizens and leading microbiologists into a frenzy. The biggest threats have been the viruses that were least expected. If you don’t see them coming, how can you protect against a deadly outbreak? The general strategy for antivirals is “one bug, one drug”. However, any small mutation of the virus might render the drug useless. Research is currently being poured into developments of a broader range of antivirals. The current hypothesis is that certain proteins inside cells are vital for virus replication. But what if those cellular proteins aren’t necessarily vital for host life? A promising target is the TSG101 protein, which is involved in the transport of viruses out of a cell. A small-molecule drug has been developed to inhibit that interaction between the protein and virus. Researchers have identified more than 30 viruses that rely on this protein, so the drug does protect over a broader range infections. One hundred percent of Ebola-infected mice survive if exposed to the drug, a day after infection. Eighty percent survive if treated two days post infection, and 40% live four days after infection. The early test results seem promising for a strong, broad ranged antiviral drug, that does not hurt the host.
The most promising broad spectrum antiviral targets the host instead of the virus. Healthy cell membranes express a substance called phosphatidylserine on their inner surfaces. When under stress from a viral infection, this substance ends up on the outer surface. All viral infections seem to exhibit this behavior, making it a key target for drugs. An antibody called bavituximab has been developed, which binds to the phosphatidylserine. Once bound, the immune system should clearly recognize the infected cell and destroy, thus limiting viral replication. This method was tested on guinea pigs exposed to a Pichinde virus. Half the animals treated with bavituximab survived, compared 100% death for the control group, not injected with the antibody.
The antibody is currently being tested for a broader range of viruses, such as HIV, hepatitis, and influenza. So far, all infected cells express this molecule on the outside of their membranes, as compared to healthy cells, which maintain the molecule within the cell. This antibody could potentially protect against all known viruses, and some unknown as well, considering all viruses are believed to exhibit this behavior. However, viruses do evolve. Could they evolve to become immune to the antibody at some point? Further testing with humans is also needed to determine any potential side-effects. But, this is one step closer to a universal antiviral.


Creating Synthetic HIV Vaccines

Contributed by Guest Blogger: A. Lee ’14

HIV is particularly virulent due to its specific attack of host immune cells and disruption of their normal function. The human body needs helper T-lymphocytes (HTL), which coordinate and activate other immune cells, and cytotoxic T-lymphocytes (CTL), which attack infected cells, to work cooperatively to defeat illness. HIV attacks HTL and through its high sequence mutation rate evades the body’s attempts to identify a parts of it for counterattack, called epitopes; these constant, minute changes in the virus also makes vaccine development difficult. However, recent technological advances have allowed immunologists to circumvent this problem through study of HIV’s amino acid sequence, or its structural makeup.
Researchers have identified key epitopes of major HIV subtypes, recognizable by HTL and CTL, and combined them into two vaccines, a synthetic protein structure to activate HTL (called EP-1043) and a plasmid (DNA segment, EP HIV-1090) to activate CTL. EP-1043 was created by cutting the DNA sequence of the 18 epitopes into overlapping sequences, fusing that with insect and viral sequences to ensure viability in a bacterium, and using this sequence in a non-deadly virus to force a bacteria to create the protein. The EP-1090 DNA sequence was created using a similar process of combining epitopes into overlapping sequences and replicating them using a process called PCR (no similar process exists for replicating proteins). Importantly, EP-1043’s protein epitopes are joined by weak bonds, meant to break and spread the epitopes through the body. Because the protein aggregates (becomes useless) at blood pH, it is packaged in aluminum hydroxide (Alhydrogel) and aluminum phosphate gels, which dissolve later.
Effectiveness of the virus was measured 39-42 days after infection by measuring cytokine (cytokines are secretions of infected cells causing immune reaction) and by measuring reproduction of splenocytes (spleen immune cells). Though EP-1090 was ineffective, EP-1043 was significantly effective in causing immune. Despite the low toxicology of the vaccine, and the fact that a true vaccine for HIV would require CTL and HTL epitope response from singular cells, this is an important step towards combating HIV.
One wonders, then, what more complex methods can be used to amalgamate epitopes for vaccines, and what method immunologists will use to create true HIV vaccines, if at all possible. This method can be used for other, less complex viruses, but does this relatively non-specific, general epitope flood lessen the necessary specific response? Can the body handle such a large, sudden appearance of viral material?


A Universal Flu Vaccine?

The flu comes back year after year, and every season we get vaccinated (well, some of us anyway).  Why do we need to keep getting a new shot for the flu while for others, like measles, we got way back in childhood and are done with it for the rest of our lives?

Our immune response to influenza involves production of antibodies, large proteins that specifically bind to the virus and help clear it out or neutralize it.  It seems like the key to influenza immunity is neutralizing antibodies, antibodies that bind to the virion and prevent it from attaching to the host cell.  You can imagine this large protein just being physically in the way, preventing the virus from binding the host receptor.  The immune response that develops from natural exposure or vaccination generates neutralizing antibodies to HA, a viral envelope protein that is necessary for attachment to the host.  I’ve mentioned HA in a previous post about influenza.  The problem is that last season’s neutralizing antibodies dont bind to this season’s virus.  Although it may be nearly identical to the virus from a past season, the new strain’s HA is slightly different, and those differences are enough to evade existing neutralizing antibodies.

Now a new approach to vaccination has shown that it may be possible to develop a vaccine that illicits broadly neutralizing antibodies, that is, antibodies that will protect against  influenza strains with slightly different HAs.  They used a prime/boost approach, in which a DNA vaccine was used to induce an initial response against HA, and then boosted with a regular seasonal flu vaccine.  The only difference between this and what is currently done is the addition of the DNA vaccine.  However the response seems quite different.  Neutralizing antibodies were generated that can neutralize a variety of different influenza viruses.  It seems the vaccine induced antibodies to a different part of HA.  Antibodies are so specific, the dont recognize the whole HA, but rather discrete parts of it.  The part recognized by these antibodies, called the stem, is highly conserved, meaning it doesnt change season to season.

This raises many interesting questions and possibilities.  Could we soon have a universal vaccine that will protect us for life or at least for many years?  Why did the change in vaccine regimen induce antibodies to a different part of HA?  Why does the current vaccine or natural exposure fail to develop antibidies to the conserved portion of HA? Will the conserved portion of HA eventually change too, if sufficient selective pressure is applied through mass vaccination?