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We are going to switch topics and go back to infections that are transmitted person to person, and we are going to start with this diagram to remind you all that, much like what Andy Morgan was talking about this morning with EBV, this is a fairly complex virus. It encodes over 70 polypeptides and has some fairly unique features that I think distinguish it even from other herpesviruses.
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This slide has a few salient points regarding herpes simplex viruses. There are two Herpes simplex viruses, type 1 and type 2. These commonly infect mucosal surfaces, skin and neural tissue. One thing that is unique about Herpes simplex relative to the other human herpesviruses is that viraemia is really not an important element in the pathogenesis of disease outside the immunocompromised or the immunodeficient host.
One of the hallmarks of Herpes simplex virus infections is the fact that the vast majority of infections are asymptomatic. It is estimated that 80 to 90 per cent of the infections are unrecognised by the people who are infected. That would seem for most people to be wonderfully blissful, to not know you are infected. Regrettably, despite not knowing you are infected, you do shed virus. And most of the transmission events that occur, actually occur as a consequence of asymptomatic shedding.
Herpes simplex, like all of the human herpesviruses, does establish lifelong, persistent infection, and we do see recurrent infections despite a full complement of virus-specific host immune responses. That raises the question: if the host isn’t able to control this virus as a consequence of so-called natural infection, can we improve upon natural infection-induced immunity to do something better? I think the success of the HPV vaccine suggests that indeed that could be the case.
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This diagram is to remind you of the pathogenesis. This is a virus that, generally speaking, starts out on a mucosal surface or as a consequence of gaining entry through small micro- or macro-abrasions. Literally within a few hours of the virus landing on a mucosal cell, it finds its way into peripheral nerve endings and very quickly, even without a round of replication in the periphery, is taken up, moves through peripheral nerves by a retrograde transport process – which is being investigated and beautifully described these days by Tony Cunningham, in Sydney, at the Westmead. It moves up to sensory ganglia neurones. In the case of genital herpes it is sacral ganglia, in the case of orolabial it is in all likelihood trigeminal ganglion.
Once it arrives at the level of the neurones, it finds neurones in one of two states. Neurones may be permissive for lytic viral replication, in which case the virus replicates, infects collateral neurones and then is spread back, in an anterograde process, back to the periphery, where it is released and replicates again at the dermal-epidermal junction, and you get the development of the characteristic lesions of herpes – or asymptomatic shedding, as the case may be.
Some of those neurones turn out to be not permissive for lytic viral replication, and those are the neurones that sustain latency. Latency is a condition that, as I mentioned, persists throughout life. If one simply had a viral burden in neurones it would perhaps be of no consequence, but periodically that latent virus reactivates, comes back down peripheral nerve fibres to the periphery and is shed, causing either disease or, potentially, transmission through asymptomatic events.
As you look at this, again I would emphasise that there is no viraemia, at least not that plays any major role in pathogenesis. Many of the successful vaccines that are in current use probably act by interfering with the haematogenous dissemination of the pathogen. It is not an option for us with regard to herpes. When you think about where you might target a vaccine to control this disease, the most obvious thing is to try to protect the mucosal surface. And again with the exception of the HPV vaccine, most vaccines targeting mucosal surfaces provide modest protection.
The alternative in this case is to try to somehow protect the ganglia or interfere with interneuronal transport. We don’t have many examples of vaccines that protect against neural infection that do not act via interfering with hematogenous spread. Nevertheless, if you could prevent latency you would not have the downstream problems of reactivation and subsequent transmission.
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Not all herpesvirus infections are genital. This is an uncommon virus, in that it causes a variety of different diseases, depending upon the portal of entry, the extent to which an individual is immunocompromised or immunocompetent, and to some extent whether it is a primary or recurrent infection.
You can see on this slide orolabial infections, both gingivostomatitis and the very common fever blisters; you see an example of herpes gladiatorum – in this part of the world it may be called scrum pox, a major problem if you are a wrestler or a rugby player; herpes keratitis, one of the leading causes of blindness in the developed world; an example of herpes encephalitis, one of the leading causes of sporadic, non-epidemic encephalitis; and then an example of both primary and recurrent genital herpes.
I should mention that in addition to clear manifest diseases caused by these viruses, there is a growing body of evidence to suggest that latently infected individuals have an increased risk of developing Alzheimer’s if they happen to be apolipoprotein E4 positive. So there is a suggestion that persistent viral infections combined with certain ‘bad’ gene combinations may increase your risk for dementias. There is also a growing body of evidence, principally coming out of Bob Yolken’s laboratory at Hopkins, suggesting a link between herpes and schizophrenia.
So when you think about the potential benefits of a Herpes simplex vaccine, they go well beyond genital herpes to potentially a myriad of other diseases and conditions.
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I want to focus the rest of the talk, however, on genital herpes. It is a highly prevalent disease. It is, quite frankly, one of the easier ones for us to be able to target vaccine clinical trials to, as a consequence of its very prevalent nature.
It can be caused by either HSV-1 or HSV-2. In some parts of the world, type 1 seems to be the predominant cause of genital herpes – the UK is one example. Japan is another, where most of the cases of genital herpes are due to type 1. Deborah Fuller, who is going to be speaking later, used to be at Madison, Wisconsin. For some bizarre reason Madison, Wisconsin, a mid-western American college town, is another place where 70 per cent of the cases of genital herpes in college students are due to type 1.
With regard to the natural history, there are recurrent outbreaks. They are painful, they are intrusive, and they are interspersed with frequent episodes of subclinical shedding. Studies coming out of Seattle suggest that if you sample people every six hours for evidence of asymptomatic shedding, you can detect shedding occurring about 30 per cent of the time. So there is a lot of virus being spread.
There is an extremely interesting body of data indicating that if you are HSV-2 positive, you are at much greater risk of acquiring or transmitting HIV. The risk is perhaps increased threefold, adding substantially to the risk of HIV.
We do have antivirals; they are useful for management. It is much like insulin for diabetes – you can control the disease but you cannot cure it. And antivirals and condoms do reduce the risk of transmission, but not completely.
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So what could we potentially expect of a herpes vaccine? Well, prevention of a mucosal infection would be lovely, because if you could prevent it at the portal of entry you would end up with no disease, no latency and no recurrences, and you would be a happy person.
Several years ago we published a review article on what you might expect of herpes vaccines. It was a consensus paper put together by experts from North America, western Europe and Australia. One of the sentences in that review article said, ‘Vaccines in general prevent disease, not infection.’ When we got back the reviews on the paper, the first reviewer said, ‘Everybody knows that. You don’t have to say that.’ The second reviewer said, ‘That’s not true.’ So, with regard to what one can expect of a vaccine, it would be interesting to have a debate in this meeting as to what we think they do and don’t do.
Nevertheless, if we could prevent mucosal infection that would be splendid. If we couldn’t prevent that and we could only prevent disease, that would be terrific for the person getting vaccinated, because they wouldn’t have to suffer from the initial infection and the consequences of the infection. However, there is the potential that, despite being protected against primary disease, if you develop a mucosal infection you will also establish a latent infection and you may have recurrences. Hence you would be a potential public health nightmare, in that you are infected but don’t know it and are potentially transmissible.
Alternatively, if we could not protect the mucosa but we could protect the ganglia, we could end up with a situation where somebody suffered herpes perhaps just once and then subsequently didn’t experience further recurrences. I will tell you that there is a body of animal and human data to suggest that, while you can reinfect a mucosal surface of an individual who has recovered from a primary herpes infection, it seems very difficult to superinfect the ganglia of an individual who has already established latency in a particular site.
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Can a vaccine protect against genital herpes infection or disease? Is the concept of sterilising immunity valid for genital mucosal infections? If a vaccine can protect against disease but not against mucosal infection, is there any reason to think it might impact latency or subsequent recurrences? What are the immune correlates of protection? Unfortunately we do not have time to address the last question.
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Can a vaccine protect against genital herpes? All of the animal data up to about 2000 suggested that herpes vaccines could not protect against infection. They certainly could protect against disease.
So two clinical trials went forward in the 1990s, one by Chiron, using prevention of infection as the primary outcome measure; the second by GlaxoSmithKline, using prevention of disease as the primary outcome measure. I want to show you the data on the GSK trial.
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The GSK trial was a very large trial. It utilised a glycoprotein D antigen that was combined with monophosphoryl lipid A and alum, their proprietary adjuvant system that they refer to as AS04. We conducted two double blind, randomised, placebo-controlled trials.
The first study was a difficult study, in that we had to enrol individuals whose sexual partner had recurrent genital herpes due to HSV type 2, but the at-risk partner not only couldn’t have HSV type 2 infection, they had to be double seronegative. So you had to find these unique people who were the sexual partner of a person with genital herpes but who themselves remained immunologically naïve.
The second study was a little easier to enrol, in that we took people of any serostatus but focused on the people who were HSV-2 seronegative.
Immunisation followed, basically, the hepatitis B immunisation regimen, with follow-up at 19 months. And, as I mentioned, the primary outcome measure was prevention of acquisition of disease.
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When we unblinded the first study, which was the consort design – a person had a partner who was known to have genital herpes, they themselves were double seronegative – when we looked at the combined data, men and women, we found the vaccine had no efficacy. But in a post hoc analysis we started looking at it by gender, and what we found was that in men the event rate was the same whether they had received vaccine or not, whereas in women we were seeing substantial protection, with an efficacy of about 70 per cent for prevention of disease in women.
We didn’t have a good explanation for these findings. There was no paradigm in biology at that point suggesting that one would expect a gender-specific effect. I will tell you that this was the first efficacy trial utilising this adjuvant system, so we were certainly in uncharted territory with regard to what to expect. We didn’t do anything with this; we waited for the second study to complete.
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When the second study was completed, and we had the data about a year later, what we observed was almost exactly the same findings, in the same population. That is to say, in individuals who were double seronegative, the men showed no benefit of the vaccine whatsoever, women again about a 70 per cent efficacy rate (actually, 73 per cent).
So in two clinical trials of double seronegative women, we were seeing a substantial protection against disease.
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What was curious was that when we looked at individuals in this study who were HSV-1 positive, HSV-2 negative, we found the effect was lost. So what we had was, I think, a remarkably unique vaccine that only worked in double seronegative women, which is a fraction of the total at risk population.
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If you looked at infection, which we didn’t expect to have any impact on whatsoever, again – as you might have predicted – in men it had no effect in either of the two studies. But in double seronegative women there was a trend towards protection, with an overall efficacy of about 43 per cent. That was something we hadn’t expected. We had not ever seen that happen in animals, and we were a bit puzzled. The study wasn’t powered to look at that, and so it certainly approached statistical significance but it didn’t reach it. Subsequent ongoing studies are sufficiently powered to look for an effect of the vaccine on prevention of infection.
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So what do we know, in terms of insights and conundrums, with regard to the first question?
Well, we know for the first time in about 80 years of attempting to make HSV vaccines that there was proof of principle, that indeed it was possible to develop a vaccine that would prevent genital herpes, albeit in this case in a very select population: double seronegative women. It prevented disease, but it also showed us that it might be possible to protect against infection.
The Chiron vaccine trial completely failed. What was unique about that was that it contained very comparable glycoprotein antigens – in the case of the Chiron vaccine it was gB and gD, combined with their proprietary adjuvant system MF59, which is a squalene oil-in-water emulsion system. They showed no benefit of their vaccine against either infection or disease. There was a trend towards protection in women, but it was not statistically significant.
So we have a number of questions that we still don’t really have answers for. Why does the vaccine only work in women? Why did the GSK vaccine work, while the Chiron vaccine failed? That may be related to the adjuvants; we don’t know. Can the limited protection against infection that we were seeing in this situation be improved? We don’t know. And is the natural history of infection in the women who received the vaccine, but who went on to become infected, different? Do they have fewer recurrences? Again we don’t know.
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Now that we had tumbled onto the fact that we were able to afford, or appeared to be able to afford, some protection against infection in women, we wondered, ‘what’s the explanation for that?’ We puzzled over whether the concept of sterilising immunity was actually a valid concept in the case of genital HSV mucosal infections.
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So we designed a study which was a bit different for us. Most animal studies immunise the animal and come in with a very high-dose challenge, and you are usually satisfied if you prevent disease. With this design you never protect against infection. We decided to do it a bit differently, and we describe this as a threshold-of-infection experiment.
In this situation what we did was to take female C57 black mice and immunise them. Although we have done this with a variety of different vaccines and have got somewhat similar results, in this case we used the same vaccine that was used in the human clinical trial.
We immunised the animals twice. Five weeks following immunisation, the animals were challenged, different groups with different titres of virus, ranging from 100 plaque-forming units up to 5x105. We next measured a variety of outcome measures.
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The one that I really want to focus on is the infectious disease 50 percentile or ID50. We also determined the dose required to cause disease in 50 per cent of the animals, the CD50. I think what you can see is that in the case of the control animals it took less than 100 plaque-forming units of virus in order to infect 50 per cent of the animals – so these animals were extremely susceptible – whereas with regard to the immunised animals the dose of virus that was required was more than 2 logs higher. The same thing was seen with regard to susceptibility against development of disease, where it was a 3 log shift.
We were really excited by these results, for a variety of reasons.
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I think you can see from these data that the vaccine is shifting susceptibility. You could certainly define that as inducing sterilising immunity, if you use a challenge virus titre that is below the threshold necessary to establish infection. We do not have data on the minimum dose required to infect humans or the maximum dose of virus a human might be exposed to so it is not possible to calculate how great a shift in susceptibility would be required to afford a true sterilising immunity.
What we do know is that vaccines are capable of inducing sterilising immunity, depending on how you define the sterilising immunity, and that below some threshold point animals will be completely protected against mucosal infection, but that if you push the titre high enough above the threshold you will achieve infection.
In terms of a conundrum, what we didn’t know at the time we completed these studies – but we do now – was what were the correlates of protection. That discussion will have to be saved for another day.
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In the real world it may be difficult to completely afford protection against infection, and it seems possible that some individuals who are immunised but who get exposed to a high enough amount of virus will become infected.
In that case what we want to know is: are they going to have the same burden of latent infection and have as many recurrences and as much asymptomatic shedding as somebody who had never received the vaccine?
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We conducted an experiment in guinea pigs. Now, the guinea pig model is unusual among small animal models, in that the animals, once they have recovered from primary infection, experience spontaneous clinically apparent recurrences that you can enumerate, much as you can in a human clinical trial.
They also shed virus in the absence of any clinically apparent lesions. In humans you would call that asymptomatic shedding. Guinea pigs don’t complain of symptoms, but it is certainly shedding in the absence of any lesions we can observe. We were able to identify situations in which animals shed virus in the absence of any clinically apparent lesions.
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When you follow these groups – in this case they are animals that either have been sham immunised or have received the glycoprotein D vaccine – what you can see in the first column is that all of the animals, when challenged with a very high dose of virus following immunisation, became infected. If you just look at the titre of virus on the first couple of days in the naïve animals, you see that it is higher than it is in the immunised animals. At one time we would have declared that success in terms of the vaccine, but they are all still infected. So in reality this is a failure. The vaccine doesn’t prevent the infection. The result is a consequence of experimental design.
When you look at disease, however, what you see is that all of the animals that received the vaccine were protected against developing clinically symptomatic disease, whereas 10 of the 11 animals that were sham immunised developed findings of genital herpes.
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If you follow these animals and you track them after they have recovered from the primary infection, a couple of things become obvious. Nine out of the 10 animals that were sham inoculated went on to have recurrences, and they had fairly frequent recurrences over about a 55-day evaluation time. Only two of the 12 animals that received the vaccine went on to have recurrences, and they were infrequent recurrences. So it was sort of a good news story: Yes, they became latently infected, but they had far fewer clinically apparent recurrences.
If, however, you look at just viral shedding in the absence of clinically apparent disease, what you see is that all of the animals that became infected shed virus, suggesting that they were all potentially contagious. If you looked at the frequency with which they shed, there was no difference. So they shed just as frequently as animals that had been sham immunised.
The interesting thing, however, was that the magnitude of the shedding episodes, the amount of viral DNA that was recovered, was about 2 logs less than in the sham group. If you can project this on to what you might expect in the human condition, what this suggests is that indeed humans may shed but they may shed less and hence be less contagious.
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If you looked at the burden of latent infection, just by pulling the ganglia out of the animals at about day 70 post-inoculation and looking by quantitative PCR at the viral DNA burden, there were about 2 logs higher amounts of virus in the sham immunised animals as opposed to the vaccine recipients.
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When you compare the sham animals with the immunised animals, it is seen that the immunised animals can certainly become infected but they had substantially less latent viral DNA. They experienced fewer clinically apparent recurrences, and while they shed just as frequently, they shed less viral DNA.
In terms of conundrums, one of the questions is: could a vaccine have an impact on public health by making the uninfected individual less susceptible – changing the threshold of infection so that it now requires more virus exposure for them to become infected – while at the same time enable the immunised individuals who are infected to shed less virus and hence be less contagious? From a modelling perspective this is not a bad situation. On the one hand, you have got people who are more resistant; on the other hand, you have got people who are less contagious.
What we don’t know is why there is no effect on the shedding frequency. We don’t understand that.
We really don’t have good immune correlates of the protection we are seeing against infection in the ganglia. Some of our data – and I will come back to this at the very end – suggest that it is all about T cells.
Finally, we impacted the burden of latent infection. Is it possible to completely prevent latency? We have some data – there is no time to get into it today – that suggests the answer is yes, it should be possible to prevent latency, even without preventing mucosal infections.
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In terms of general insights, we do know that the development of an HSV vaccine is feasible. We know from the animal studies that vaccines induce protection by shifting susceptibility to mucosal infections, but that that protection can be overcome by a high-dose challenge. We know that vaccines, again from animal data, can impact latency and recurrence without preventing mucosal infection. And that speaks a great deal to what the primary outcome measures should be in subsequent clinical trial designs, because prevention of mucosal infection still may be a bar set a little too high.
As to protection against ganglionic infection, studies utilising animals depleted of either CD4s or CD8s suggest to us that prevention of ganglionic infection is all about T cell responses. You can get good protection with either CD4s or CD8s. (I’m sorry, there is no time to go over the data.)
Interestingly, in animal studies using uMT antibody-deficient mice, protection of the mucosal surface against herpes is all about antibody, which is something that we would not have expected, based on the difference between the Chiron and GSK studies.
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We still don’t know the basis for the gender-specific protection. We find it intriguing. There have been subsequent data on the durability of the BCG vaccine over many years, indicating that there is greater durability of protection in women than in men, so at least two studies suggesting a gender-specific vaccine effect.
How important is the adjuvant? We thought it was very important; now we are not sure.
What is the role of mucosal immunity? Our data suggest that it is critical, that it is really all about mucosal immunity and we have probably been measuring the wrong thing all these years by looking at circulating antibody.
We don’t know whether resident T cells are important in protection against ganglionic infection. If they are, getting them in there may be tricky.
We don’t know the best vaccine strategy. Quite frankly, inducing broad, robust responses to everything seems like a good idea at this point, but, as was suggested by Ian Frazer this morning, we usually find something that works and then work backwards to understand how. That is the sort of situation we are in at the moment.
And as a final conundrum, the one I suggested at the beginning, it would be great to have a vaccine to protect against non-genital HSV infections as well.
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Just to wrap-up on the GSK vaccine: neither of the two studies that we conducted met the primary outcome measures to support licensure by the Food and Drug Administration. A third efficacy study was started in January 2003, and finally closed enrolment last year. It involves almost 8000 young women aged 18 to 30. Outcome measures are going to be not only prevention of genital herpes disease in these young women but also prevention of an infection as demonstrated by seroconversion. There will be substudies looking at shedding from those volunteers who become infected. And in this population we will be able to determine whether the vaccine has benefit against both HSV-1 and HSV-2. The first two trials were designed to look at effect on type 2 only.
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Finally, what can we expect? Well, we will get the results of these phase III trials. I should point out to you – it wasn’t mentioned this morning – that the GSK human papillomavirus vaccine, which I think is approved in Australia, contains the same adjuvant system that we have been using for the herpes vaccine. So you could well imagine that, if this vaccine gets approved, what you will see is ultimately a combination HPV-HSV vaccine targeting women. But the large efficacy trial under way is pivotal for licensure.
There has been a very large study of 8000 to 10,000 women and young girls that shows it is both safe and immunogenic in younger women. Basically, we will be targeting the same age group as targeted for the HPV vaccines.
There are proof of principle studies ongoing at the moment, with DNA vaccines – the former PowderJect, later PowderMed, now Pfizer Vaccines have those studies underway – as well as heat shock protein therapeutic vaccines.
We really need more work on prophylactic vaccines. The GSK vaccine has too narrow a spectrum to be useful in places like Sub-Saharan Africa, where everybody is going to be HSV-1 seropositive, and clearly if what we want to do is use a genital herpes vaccine as a secondary prevention strategy to control HIV – it would be nice to have a vaccine for all women.
And we certainly need more research on STD vaccine acceptability.
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I have felt for most of my career like Sisyphus. We keep pushing this thing further up the hill, and every time you think you’re at the crest it rolls back down over you. So I felt I needed to actually acknowledge Sisyphus as a colleague and collaborator, along with a large number of people including, as I think you will notice on this list, Tony Cunningham and Adrian Mindel, who have been long-time collaborators in this area.
Discussion
Question: I suppose I should start off with the obvious question. Why is HSV-1 seropositivity an inhibitor of immunity against HSV-2?
Lawrence Stanberry: You know, it’s a great question. I’ll give you my bias. I think that we have got a confounder in there. I think there are a large number of individuals who have unrecognised HSV-1 genital herpes, and so they have got a great robust mucosal response going on, down where HSV-2 is generally going to be introduced. And so I think that what we have got here is a very difficult situation where it is probably not HSV-1 circulating antibody that is important; it is probably mucosal responses and cross-protection.
Half the studies in the literature suggest that HSV-1 affords protection against HSV-2 infection; the other half suggest that HSV-1 infection does not protect against HSV-2 infection. And there is no easy way for us to get a handle on asymptomatic type 1 in the genital tract. I think that is the explanation.
Question: Lawrence, it’s lovely work, and I assume you will have looked at different antibody subclasses.
Lawrence Stanberry: We have been looking at subclasses, we have been looking at T cell responses. We can’t find a difference between men and women, if you’re thinking about that as the question. We did not, however, look at mucosal responses.
Question (cont.): I wondered whether there is a difference between the double negative women and the 1-positive women, in the duration of an IgA or IgM response that could affect, basically, how much antibody gets into the mucosa.
Lawrence Stanberry: In our studies we didn’t look at that. The Chiron studies did examine the levels of antibody, both IgA and IgG, in the genital tract. Rhoda Ashley Morrow did that work, but could find no correlation between protection and titres that were present there. So we are missing something; we simply don’t know what it is. Perhaps it is going to turn out to be subclasses and we’re just not clever enough to pick it up. We have not been looking at antibody affinity, and so that is clearly the next thing we need to be looking at.
Question: This is just a comment along those lines. In cervico-vaginal secretions from both humans and also mice and rats, IgG is more likely to be the most common isotope present than IgM, whereas early work that we did with males for rats, mice and rabbits showed that serum IgG does not get into the male reproductive tract, or at least it is highly retarded. So did you look at IgG versus IgA levels in seminal plasma and, say, cervico-vaginal secretions as a possible answer to the gender difference?
Lawrence Stanberry: We didn’t do anything with the males except bleed them, so we don’t have anything around seminal vesicle fluid. We have speculated – and it is pure speculation, since this is a new adjuvant system that we don’t have efficacy data on – that because it induces fairly robust T cell responses it could be that women are simply primed to make a different type of response than men to this adjuvant system. That is one thing that could easily be studied.
The other possibility is that it really has to do with the pathogenesis of infection. In women, infection typically would begin in a mucosal surface; you could bathe that surface with antibody. Men, in all likelihood, become infected not through urethral openings but through micro-abrasions, and the extent to which we can protect them is really unclear. So it is a great question and we will keep looking.
Question: I am so happy to hear that there is a T cell directed vaccine at work here. The next question, though, is: is there an HLA association with protection?
Lawrence Stanberry: We’ve not looked. This is a single glycoprotein, and there is a distinct possibility that we have got people out there who, when it comes to the T cell responses, are simply non-responders. That would be a fairly easy thing to map.Visit these websites
The Sir Mark Oliphant Conference Series is supported by the Australian Government under the International Science Linkages Program.
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