SA Vaccinology Update: Associate Professor Ann Koehler Quotes - - PDF document

SA Vaccinology Update: Associate Professor Ann Koehler

Quotes transcribed from video presentation: https://www.youtube.com/watch?v=Nuucpl_NUaI Pertussis and pertussis vaccines, being something that has captivated my attention for quite a few years, and particularly since the outbreak that began in about 2009. So, it’s caused by this little gram negative bacteria (and I’m a microbiologist so I can talk about this) Bordatella pertussis which is highly infectious. So there’s this magic number called R nought, which is the average number

• f people that a case will in infect in a naïve population, in a susceptible population. So for Pertussis that’s

estimated to be 12-17. For measles it’s about 18, we know measles is highly infectious. Compare that with ebola virus, which everyone’s getting excited about, about 1.7-3 at the most. So this is what we’re dealing with this infection and we think the infectious dose is probably also very low. 1:12 It’s a problem because neither natural infection nor vaccination give long lasting immunity. So if you don’t get immunity from the infection you’d be pretty hard pressed to get it from a vaccine. So people get re-infected. There’s always going to be a reservoir of infection somewhere, and it’s only in humans, so other infections that we deal with like smallpox we were able to eradicate because they were only in humans, it was only in humans and we had a good vaccine that induced immunity. 1:48 But with pertussis, we don’t have a vaccine like we used to. You know, we’re used to use vaccines that induced long-term immunity, and I think over probably the last 5-10 years we’ve realised, particularly with the acellular vaccine, that we’re not getting that level of protection. So we really have to think hard about what we’re doing about pertussis vaccine.

2:17 Susceptibility is universal in unimmunised people and in the pre-vaccine era everybody got it by the age of five. It was one of the famous diseases of childhood, and for a long time people thought that it was only a disease of

• childhood. They often didn’t recognise pertussis in older people.

2:42 There’s a secondary attack rate in households of over 90%, so you can see why really everybody got it early. The incidence is highest in the first five years, except where you’ve got really, really, effective infant immunisation programs. 2:58 But what we’ve seen is a shift to older age groups, which a few people have alluded to here. However, I’d like to just raise in your heads the thought that maybe there’s a few diagnosis issues that are contributing to that picture. 3:14 And diagnosis is based on a number of tests. So clinical diagnosis – those of you who work in clinical practice know the three phases of the illness – so there’s that early non-specific catarrhal illness, then there’s that classic whooping cough with the inspiratory whoop and post-tussive vomiting, and then a convalescent phase that often has a relapse of that second-phase symptoms. But this classical illness, it appears, is really only in the older children – sort of infants and the older children up to adolescent age. 3:56

So babies simply might stop breathing, and adults can just have a prolonged coughing illness, (4:02) so for a long time people didn’t think that adults got pertussis because they just got this cough, and adults get coughs for lots of reasons. Then there’s culture. And this is Bordet Gengou agar plate, which is for culturing Bordatella. It has to be made up within four hours of use, and these days with laboratories all being centralised and often not on site, that’s just not feasible any more. And apart from that it’s a very expensive way to practice microbiology, so hardly anybody does culture anymore. There’s still a few good children’s hospitals who still do this, and it probably doesn’t matter except that if we start to have concerns about antibiotic susceptibility we might want to get more culture specimens, but even with prompt culturing at the bedside fresh cultures, it wasn’t easy to grow this bacteria. 5:10 So then serology came along. Serology is smoke and mirrors stuff I hate to tell you. It’s really very difficult to interpret and subjective for many diseases - and pertussis is one of the worst. So in early infection, often you haven’t got antibodies so it’s unreliable. When you need it the most you don’t know. Anyone who’s worked in a lab knows that getting that second serum – for ped serum to see if you have seroconversion or a four-fold rise hardly ever happens. It’s very unreliable in infants under two years of age, and they’re the ones really who are the most clinically affected group that you want the diagnosis for. And in serology it’s also difficult to distinguish past infection from current infection, from vaccination - so it’s not very useful, it’s not timely and it’s certainly not the test of choice.

6:08 So now we have Nucleic Acid Testing, which is sensitive. It’s specific, it’s fast and it is the test of choice. But it can’t tell infection from carriage, and one thing that has come to my attention is calls from GPs who say “one child in the family had pertussis and so I swabbed all the others and they’ve come up with positive PCRs, do I treat them or not?” So we do get a certain level of asymptomatic or very mild infections that probably don’t need treatment - they’re probably infectious. What does that test result really mean? Because PCR testing is easy and not invasive – just a throat swab, or a nasopharyngeal swab you get a lot more testing than you do if you have to send that little 18 month old baby to get blood taken. Not that that’s a bad thing but it does distort our epidemiological information. 7:09 Now pertussis isn’t the most preventable of the vaccine preventable diseases, as you all know, so even though we’ve had this vaccine since the 1940s - it’s been in our immunisation program since the mid 50s - it is the most commonly notified vaccine preventable in Australia over the past 20 years, and probably in all of the developed

• world. From 2006-12 there were epidemics in all jurisdictions and we were all using acellular vaccines (and I

think I saw Stephen Lambert in the audience who would have a few things to say about that) but the average annual notification rate was more than 2.8 times that of the previous decade.

7:54 In contrast though, hospitalisation and mortality rates remained the same. So we were probably just detecting a lot more pertussis as well – there were more cases but there weren’t more serious cases. 7:11 Now, if you look on our SA Health website you’ll have seen this slide because we put it up every week, and on the right hand side it creeps out a little further, but it shows that huge big outbreak we had starting with the pandemic in 2009 and in that pandemic we got a lot more PCR testing done, and also babies with pertussis got tested (looks at watch – “I’d better talk a bit faster”). We certainly had a lot of pertussis cases and I’m using data really from that outbreak period because as you can see there’s not really a lot to talk about since. But what worries me is we are here, are we going to go up again? and we must be going to. 8:56 Just to show you our testing, this was back at the end of 2010, so we were getting half of our testing from PCR and now it’s much more than that, so we’re probably detecting a lot of cases that wouldn’t have been detected previously, simply because people will do that test.

Data from that time in South Australia was in the enviable position of having an infection rate of 448 – a notification rate of 448.8 per 100,000 – for 10,000 sorry – which was many times the national average and we were the world leaders at that stage. We had four deaths over the previous 20 years, but only one death during that huge outbreak in an infant in South Australia, so even though one death is one too many, I think it was more that we had very very good data capture, and South Australia’s got the best notification system in Australia, because we have both laboratory notification and doctor notification, so we don’t very much miss a case, whereas other states certainly do. If a doctor doesn’t do the test they never hear about it – they’ve only the laboratory notification. So we have very good case ascertainment and so even though we had such a big

• utbreak we didn’t feel terribly guilty about what we were doing.

10:24 We were under a huge amount of pressure to introduce a cocooning program and we resisted that because our data didn’t suggest that it was going to work. 10:35 And this was the data that I think was the most convincing. If you looked at our childhood notification – so these were previously vaccinated cases in children under 12 years of age – so 2,500 cases and more than a third of them had had five pertussis vaccinations. This was when there was still the 18 month dose. 60% had had at least four, (11:03) 90% were fully vaccinated – they’d had three vaccinations.

11:10 So clearly the vaccination wasn’t as effective as we’re used to vaccines being. It wasn’t preventing infections in most people who got it. And people then began to say “well, you know, with a highly vaccinated population most

• f your cases will be vaccinated”. No, we rejected that because we certainly don’t see that with measles, we

don’t see that with hepatitis A – we don’t see that with good vaccines. 11:37 So we know pertussis vaccination doesn’t prevent infection so we could not see how it could be all that good for a cocooning program that was meant to prevent infection all around a baby. 11:50 If we looked at our hospitalisations for pertussis there was the peak in the under one year old group. That second peak at the six to nine year old group – that’s five years put together so it’s really much lower for an individual year. And what I haven’t shown on this slide is that there’s actually also an increase in older people, in elderly people. We get quite a lot of pertussis hospitalisations and even a few deaths in that group - but nobody cares about them as much as a baby. And particularly in adults with neuromuscular disorders, they really do badly with pertussis because they can’t cough very well. 12:32 But certainly the vaccine is very good at preventing severe complications, so the hospitalisation rate in children up to the age of 24 months, where we had vaccine coverage of about 92.5%, more than half the cases occurred

in the rest of the people who weren’t vaccinated. So that other 7.5% was where most (half) of our cases

• ccurred. So we know it reduces severe infections, and that it’s good for reducing hospitalisation.

13:10 So cocooning – there’s evidence, a number of papers that have looked at where babies get their infections from, and quite a few different studies – up to 75% of infants are believed to get it from a household contact, most commonly a parent, often the mother, and the global pertussis initiative during that major international outbreak thought that, notwithstanding the absence of outcome and cost-effectiveness data, if you can save just one life it was worth doing it. It’s not actually the way healthcare works, but anyway. 13:48 It was proposed as a strategy to try and prevent deaths in children who were too young to be vaccinated, because it’s a horrible thing to see a child with pertussis, a baby with pertussis. We wanted to minimise exposure by ensuring that nobody around the baby would be infected and therefore infectious, and so the idea was to reduce risk by vaccinating mothers, but alternatively in the latest handbook the option of maternal vaccination has also appeared.

14:30 The cost analysis study of cocooning eventually came out in late 2011 from Canada, and the conclusions were that the immunisation of new parents with pertussis vaccine is expensive and resource intensive. The number needed to vaccinate was 10,000 to prevent a hospitalisation, 100,000 cases – this is people to vaccinate – to prevent one infant intensive care admission, and more than a million to prevent one infant death. 15:00 Now when you factor in that the vaccine is sort of $35 - $50, that’s $35 – $50 million to prevent one infant death. It doesn’t get past PBAC I can assure you. So that’s why it was never funded nationally, even though that information wasn’t around people knew it was going be very expensive. But even if it was favourable, it just doesn’t happen. You just cannot implement that program well, and particularly it’s really hard to get anyone but the mother vaccinated, and particularly fathers. 15:35 So, maternal vaccination was then proposed, and it has been now recommended in a number of countries. And we were assisted with getting some evidence about this by a large outbreak in Britain, which was published in Lancet earlier this year by Dr Amirthalingam from the Public Health Agency (and her group).

16:00 So the UK had this large outbreak which was declared back in, I think it was about April in 2011 – and this is October 2011 - and at that stage they decided to fund a maternal vaccine for women in the third trimester of

• pregnancy. So this was great – we got some data.

16:25 It was also motivated by the fact that they had 11 deaths, sorry 14 deaths, in infants under a year of age. They had 6 deaths in 2011 and then there even more deaths in the following year, so they funded that program and got a lot of data (new slide) which we could look at.

16:52 Now their cases showed clearly that it’s the babies who haven’t had three doses of vaccine who are the ones getting the highest burden of disease, and we know that they’re also the ones who have the poorest prognosis. 17:10 So they studied nearly 27,000 women who had a live birth in that program which commenced in October 2012, which was also in their epidemic peak – but that’s the way it happens. We’ve still got some good data. And for the first nine months they saw the greatest proportionate fall in cases – this is in under 3 month old children – a 78% reduction in cases and a 68% reduction in hospitalisations in those babies whose mothers had been vaccinated in the third trimester of pregnancy. (17:47) Which is dramatic. And this under 3 month of age group was also the only age group in which there were fewer cases in that year than in previous years. So it was actually definitely reducing the number of infections. 18:06 And this was only with about an average of 64% vaccine coverage, so not even the sort of 90%-100% that you’d be hoping for. And somebody’s mentioned earlier the effectiveness in infants was around 90%-91% if you just looked at under 3 months and 90% if you looked at children under 2 months. 90% is a very good effectiveness for a vaccine.

18:35 And they also found that the vast majority of mothers were in favour of this, so it’s really only the orange and red

• nes who were probably resistant to pertussis and they probably haven’t seen a baby with pertussis (or they

might have changed their minds). 18:56 So other important considerations – and I think someone’s mentioned this too – vaccine safety. Of course, you worry about vaccinating pregnant women. They didn’t identify any vaccine safety issues, so they are still gathering data on that – and the other comment about the possibility of it blunting antibody responses to other vaccines that are given in that infant age. 19:25 So far they haven’t seen any relative increase in cases of those other vaccine preventable diseases, which suggests that it’s not having a significant – a clinically significant effect – on the immune response, even though it might give a measurable antibody change, but they are continuing to follow that up. So maternal vaccination is the only way that you can protect infants from the time of birth because you have to get the antibodies into the baby. 19:58 It’s not actually that useful to get the antibodies into somebody else if it’s not preventing infection and infectiousness.

20:05 And you have to get the babies through the period when they’re at the highest risk of death and severe

• complications. And severe complications we’re talking about with pertussis are: hypoxic brain damage, epilepsy,

intellectual deficit, brain hemorrhage, retinal hemorrhage, hernias. So they’re not trivial complications. The vaccination in the third trimester gave the best transplacental transfer of antibody. There’s been other studies that have looked at cord antibody levels from before immunisation, before pregnancy and they’re not really at protective levels, so this is the best way to get as much antibody as possible into that baby, and it gives that protection until they start getting their vaccines. 20:58 And of course there’s the added benefit of a cocooning effect where these women are not likely to be a source of infection for their babies or other children. So it’s recommended in the UK, USA, Canada, New Zealand and Belgium in every pregnancy, to answer the question someone got before. But that’s for an outbreak measure. Whether it would still be recommended when there isn’t an outbreak in all of those countries, I’m not sure, and it would be good for a recommendation for it in every pregnancy if we had a single antigen vaccine, because people are going to get pretty sore arms with all that tetanus antigen. But that’s the current recommendation. It’s also, the reason to see a single antigen vaccine on the market, and I’m kind of hoping that if enough countries are recommending maternal vaccination that there might be interest in vaccine manufacturers to work on that – and there may be. They’re coy about things like this. So that’s my discussion about this, and I apologise if I didn’t give as much detail to that. I was originally asked to talk about cocooning, but I said I wouldn’t talk about cocooning unless I could talk about maternal vaccination as

• well. So thank you.

Q&A Q: Hi, my name is Kate. I currently a pregnant immuniser. so my question is …….. I myself had a Boostrix back in April/May of this year and now, obviously, we’re talking about maternity immunisation. Is it safe for me to have another one in my third trimester? A: I doubt whether anybody would be recommending that. I’m sure it’s safe but it’s a grey area and I certainly wouldn’t be recommending that you had another one so soon. Q: Hi, my name’s Kate too, and a similar question. If I’ve got a very well informed mother who has no objection to sore arms and no objection to paying lots of money, do I tell her that the official recommendation is that she has a pertussis immunization with every pregnancy? A: Yes, Q: She’s very well informed and she’s googled. (?) (laughs)

A: I can’t say what’s going to be in the official ATAGI recommendations, but certainly you would be recommending vaccination in the third trimester. ATAGI’s met recently and were going to discuss the stage at which it’s given – which weeks – and I wasn’t able to get to that meeting because of Ebola, but I don’t know if someone can comment on that? Ross Andrews from Menzies Health Research -the chair of ATAGI. The process is that the Handbook is an NHMRC endorsed guideline, and so to make changes to the Handbook, for a major change it goes through a consultation phase, so as of right now there is no recommendation from ATAGI that we should get the vaccination for every pregnancy. But that is a recommendation in the UK. There’ll be a public advertising of the recommended changes to the Handbook which includes pertussis and other changes to other major components, which invites community consultation over a month and that’s. It does slow the process down but it’s an important part of developing guidelines involving the NHMRC because it puts the recommendation out and exposes it to criticism and comment, and there are always lots of comments and that’s intended to try and make the Handbook a more usable document. So my short answer is – right at the moment there is no recommendation to get the pertussis vaccination every pregnancy, but that is the case in the UK, there appears some data for the person who was vaccinated recently – there is some data that if you’re vaccinated within 13 months of your pregnancy that there is good antibody transfer through the placenta. Whether that is sufficient and related to less disease, that’s a different question. Q: So just a quick question - third trimester is fairly broad, so does it matter? A: That has to be specified in the Handbook. I think it’s usually about 26/28 to 32 weeks but I’m. Actually in the British study there was one death in an infant whose mother had been vaccinated and that vaccination had

• ccurred a week just prior to delivery, so you would want to get the vaccination early enough in the pregnancy to

allow for premature delivery so that the baby would still be protected, and to give time for maximum response. But timing is a bit difficult Q: With health care worker vaccination policy it’s recommended for health care workers to have the pertussis

• vaccine. Have we got funding for that?

A: Funding for health care workers is an employer responsibility, it’s an Occupational Health & Safety issue. So it’s not funded by the immunization program, and it’s not State funded, except for the State funded hospitals. It’s an OH&S issue. Q: Have we got funding though for State for health care workers to be vaccinated? A: Hospitals have budgets. Just like they have to have to allocate a budget for personal protective equipment, training etc. Q: (Inaudible question) A: No it does go under individual hospitals as well. It certainly does. Last question (?) from People’s Health Services, Pt Augusta. We promote vaccination with the flu needle for pregnant women. Just wondering is there a recommendation for Boostrix as well, would we be doing them both in the third trimester or vaccinate for the flu throughout the pregnancy? A: Yea, I would not be delaying the flu vaccination till the third trimester because women don’t wait to the third trimester to run into problems with that. So