TB vaccine research update - Part 2

In this second blog of a series on the progress in TB vaccine research, we going to take a walk through the forest of this research, replete as it is with trip-hazards and quite dense vegetation. And at its end, we will offer a moxa-related observation that we feel is highly relevant.

But first, we need to understand more about this vegetation - why it is so implicitly dense and hard to penetrate, and what issues we need to clarify to find our way through it.

BCG- a TB vaccine already exists...

The first is that, yes, a TB vaccine (the BCG) does already exist – and moreover it’s done so for 104 years. The issue is it has never been anywhere near as good a vaccine as might be expected, nor as is commonly believed.

Yes, BCG affords limited vital “lifesaving protection” against TB to at-risk infants who receive it soon after birth in most TB-endemic countries. Sure, its protectivity for them could still be improved, but currently it does do pretty much what it's known to do - protecting these little ones at a particularly vulnerable time of life from being infected by a family member (and so probably die). BCG also exerts some curious so-called ‘nonspecific effects’, incidentally, which have been shown over the years to curiously protect children against infectious diseases other than TB during infancy. In some studies, it’s even been linked to significant reductions in all-cause child mortality, though exactly how it does this is remains a matter of conjecture.

The problem is that BCG doesn’t protect either adults or adolescents against pulmonary TB, and this has been well-known for fifty-odd years. This is why there is a need to develop new TB vaccines, “particularly ones that can prevent TB in the middle age groups that account for most of the world’s incident TB disease and deaths each year and therefore most onward transmission”. (All direct quotations in this blog are directly taken from the TAG TB Vaccine Pipeline report, by the way).

The point is that, if such protection can’t be elicited from a new vaccine, it’s generally accepted that the goals of eradicating TB will remain biomedically out of reach because the cycle of ongoing infections (most of which are hidden by being sub-clinical or latent) will inevitably persist ad infinitum.

The Two-tier nature of TB infection

Unfortunately achieving such protection from TB in older age groups sounds a lot easier than it has proved to have been despite all of the might of modern medicine and vaccinology, and this is down to the two-stage nature of TB infection, its chronicity, and TB’s associated epidemiological realities.

Firstly, a TB infection is not as black-and-white as most pathogenic infections. You can be infected with the TB mycobacterium and yet have no symptoms – and this is the case with the vast majority of TB infections (of which there are estimated currently to be approaching 2 billion – or 25% of mankind). Most of these infections thankfully remain ‘sub-clinical’ and asymptomatic and are often referred to as ‘latent’, but these infections can still be confirmed by a positive ‘IGRA’ test (currently the best test available for this disease state). This test, if positive, confirms that you are infected with TB but it does not confirm that you have active disease – it only confirms that you’ve been exposed to the TB mycobacterium and have been infected. It indicates, in fact, that your infection is inactive at the time of the test and is almost certainly ‘walled off’ in the lungs by your immune system - hopefully for the duration.

Unfortunately, this isn’t always the case. In a small proportion of such cases, the infection breaks out of this latency and ‘re-activates’, and then it begins to manifest as the potentially merciless lethal disease that we should all understandably fear. The folk in whom this pathogen has reactivated are classified as having ‘incident’ TB disease and it’s generally believed that it’s only when it’s in this re-activated state that TB can become infectious to others (although rather worryingly, this belief is currently being challenged by some disturbingly convincing research).

Be that as it may, these ‘two-tiered’ conditions of infection constitute the primary reason why TB vaccine implementation is, and always has been, something of a challenge. In most infections for which vaccines are considered necessary, the potential vaccinees are assumed to be ‘naïve’ to the infectious pathogen (in other words they are not carrying an existing infection and ao are intended to be protected from a primary infection by the vaccine – think measles, for instance, or smallpox, mumps or even HIV). The problem for TB vaccine researchers is that a very significant proportion of those needing protection from TB in the adolescent and adult population can be expected to be already sub-clinically infected (about 2 billion, in fact, as mentioned above). In fact, in those countries where a new vaccine is most needed (i.e. in countries with significant TB epidemics) this status of existing infection may even amount to a majority of adolescents and adults.

Generally, vaccines aren't expected to protect against an existing infection (in fact it amounts to bad practice to knowingly vaccinate anyone who has an existing infection because doing so may either stoke an aggravation of that infection or provoke mutations in the pathogen that caused it with very serious epidemiological consequences). It has never been an accepted practice, for instance, to use BCG on anyone known to be already infected with a sub-clinical or latent TB infection.

This means that it is asking a lot for TB researchers to find us a vaccine that both protects those who have never been exposed to this pathogen (as the BCG does for infants, thus preventing a primary infection ) and those who have already been infected but have no signs of active disease (thus preventing the disease from developing into its active state).

The additional aspect of those who have already recovered from TB

On top of this, there exists within this second group of 'already infected' a significant subordinate cohort who have not just already been infected, but who have also had the fully re-activated dangerous disease, and have recovered from it with a course of TB drugs. This is a cohort that is being added to each year to the tune of about 6 million cases who complete treatment  – though what number the total prevalent number of this cohort might consist of is anyone’s guess (probably around a couple of hundred million wordwide). The key thing to appreciate is that these recovered cases are unfortunately also well-known to run specific risks of relapse (often, unfortunately with a drug-resistant strain) – and as a result, they need as much or more protection from such a relapse of disease as any other at-risk group (arguably more protection in fact because their risk in some sense is higher).

As the Report states unequivocally, “it turns out that disease recurrence among people who have already had TB is a more frequent event than TB disease itself, and [what’s more] most people who develop recurrent disease do so within the first year of completing treatment”.

As we have already suggested, and as we can now really begin to appreciate, we are undoubtedly asking a lot from any new TB vaccine!

This last group, however, (particularly the ‘recently recovered’) do provide an interesting and exciting window of opportunity for TB researchers. Because TB is such a slow-moving disease, the timescales required for harvesting any positive or negative clinical significances in clinical outcomes post-vaccination is normally lengthy compared to other infections (if it takes years for a TB infection to become evident it will equally take many years for any meaningful comparative data to emerge from a vaccine study). This makes TB vaccine research normally not just lengthier and very challenging to manage, it also makes it much more expensive compared to researching vaccines for other much faster-moving pathogens. If you then factor in the existing trail of failures into the story of this research, this explains another reason why TB research is not that attractive for funders.

But it’s been more recently realised that, if most disease recurrence occurs “within the first year of completing treatment”, then these recently-recovered cases comprise an ideal group for recovering primary outcome data from because the monitored periods can be significantly shorter. Primary outcome efficacy data should emerge in a year or two at most, making for faster results and less requisite funding.

H56:IC31 -what does it tell us?

The TAG Vaccine Pipeline Report also points out that even negative results can offer researchers new insights into what might be adapted and prove more more effective, and an interesting example of this is trial H56:IC31. This was a vaccine candidate that had been showing good promise after Phase 1 research and a subsequently successful Phase 2 Proof of Concept trial. Unfortunately it has now dropped out of the race because of clinical failure at Phase 3.

So what might this failure be telling us? Well it could be telling us a lot more than even TAG are considering.

This trial looked at exactly the group that we have just been discussing as ideal research candidates (the recently recovered). The research was set up to assess whether vaccination with H56:IC31 at the end of standard TB treatment lowered the risk of recurrent or relapsing TB occurring when compared with placebo. Participants were easier to enrol because they were completing a course of TB treatment so could also be expected to adhere to the study's design in which they received two doses either of H56:IC31 or placebo — one dose during treatment, and one soon after. They were then monitored for recurrent disease for the next 12 months.

Sadly, the results were very disappointing: in the end recurrent TB (of the same strain) was found in 23 of the 400 people who received the vaccine but only in 14 of the 406 participants who received the placebo. This amounted to a negative efficacy of 73.8%, strongly suggesting that the effect of the vaccine may have actually increased the risk of recurrent TB driven by relapse.

Was this increased risk specific to this specific vaccine itself, or might it be typical of any vaccine being tested for evidence of relapse in a similar high-risk cohort? Of course, researchers are trying to figure this out, not least because currently there are existing vaccine trials in progress that are employing the same strategy.

Going from a positive outlook to a final negative outcome is unfortunately far from atypical with TB vaccine research, but with each failure more is learnt, and so we may still be getting nearer to the holy grail of a protective vaccine for humankind's most lethal infectious foe.

The reality behind the failure of this trial may relate to the state of the host immune systems of those enrolled in the trial. It's a strong probability that the immune systems of the subject cases were already strained before their TB was originally diagnosed. This is probable because it's well known that latent TB is more prone to break out and reactivate from its sub-clinical state if the patient has weakened host immunity. But the relative strength of this host immunity is unlikely to have been strengthened at the end of six months of strong multi-drug antibiotics that have effectively ‘cured’ the disease. It's far more probably going to have been further compromised, which is almost certainly why diagnosis of relapsed TB disease is a "more frequent event" in these recovered cases than the general incidence of 'normal' TB disease. This known higher relative incidence of relapsed TB occurring post-treatment strongly suggests that this may be the case and, if it is, the researchers may well have been further insulting their subjects' immune systems with the immunological effects of two doses of vaccine during and just after their drug treatment. In other words, this probably explains why the trial design might have increased the risk of relapse as the data suggests and failed to decrease it as was expected.

Might moxa improve the odds, Perhaps?

With our Moxafrica hats on, we might thus argue that three months of moxa during drug therapy and before vaccination might just provide a feasible way to switch the odds back in favour of the vaccine as was originally anticipated to be the outcome.

We hope that a vaccine researcher might just come across this observation and engage with this idea because moxa would be simple and extremely cheap to add into any research programme.

If you know anyone in this field, please, please share this blog with them. Moxa might make a difference in another study!

In the next blog in this series, we will take a brief look at what trials are still out there and discuss their prospects as well.