With all the hype regarding COVID-19 and a vaccine that may or may not be coming soon, we can use the story of RSV as an object lesson. Why do we give passive immunization to preterm infants against RSV rather than a vaccine?
RSV vaccines have been produced in the past, but there was significantly worse illness among babies who became infected despite vaccination. The vaccine was an inactivated virus but triggered “a nonprotective antibody response and CD4+ T helper priming in the absence of cytotoxic T lymphocytes. This response to vaccination led to a pathogenic Th2 memory response with eosinophil and immune complex deposition in the lungs after RSV infection”. Which is a phrase that I quote directly from (Acosta PL, et al. Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease. Clin Vaccine Immunol. 2015;23(3):189-95.) because I understand little of it, immunology was invented after I went to medical school.
Anyway, I can understand that under certain circumstances a vaccine could make things worse. As far as I can see, the trials in which the enhanced disease that occurred in vaccinated children led to the trials being stopped, and I don’t think a vaccine has ever actually been licensed as a result. Which makes me grateful for the FDA and other agencies around the world that require good evidence prior to the widespread use of a drug or vaccine. (In contrast to the claims of the antivaxers). So prior to rushing to introduce a vaccine for COVID-19 we need to be sure that it is safe and effective. Especially as severe cases of COVID seem to be associated with excessive immune responses, so there is a real possibility that a vaccine could make things worse at least for some recipients.
Newer candidate RSV vaccines will also have to be tested in adequate trials before we can be confident that they work and are safe. Vaccinating mothers is one possible way of getting around some of the problems, (Madhi SA, et al. Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants. N Engl J Med. 2020;383(5):426-39), However in this trial among 4,500 mothers who either received a vaccine based on the RSV fusion protein (F) or a placebo at between 28 and 36 weeks gestation, the overall reduction in clinically significant RSV disease in their infants during their first 90 days of life was from 2.4 to 1.5%. Which was not enough to conclude adequate efficacy, there were some signs of benefit, in terms of hospitalisations and severe disease, but not much more than about a 40% reduction for either.
For now then, I think we will be continuing with passive immunization while other candidate RSV vaccines (and there appear to be several) are being tested. Unfortunately that currently means monthly IM palivizumab injections at an exorbitant price, and a lot of discomfort. One improvement in passive immunization would be an antibody with a much lower clearance, such as this one (Griffin MP, et al. Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. N Engl J Med. 2020;383(5):415-25) so that a single dose would last the whole RSV season. In this trial, 1453 infants who had been born preterm (29 to <35 weeks gestation) but were not eligible for RSV prophylaxis according to their local guidelines were randomized to receive one dose of the new long-acting antibody nirsevimab, or placebo in a 2:1 ratio, if they were under 1 year of age at the start of RSV season. The primary outcome was the occurrence of RSV disease needing medical attention during the first 180 days, which was substantially reduced from 9,5% to 2.6%, and hospitalizations for RSV bronchiolitis were reduced from 4.1 to 0.8%.
I have little trust when it comes to big pharma, and I give you this prediction, that nirsevimab will cost substantially more than palivizumab. Probably the producers will calculate the average number of doses of palivizumab that babies receive (which is probably about 3.5) they will then price nirsevimab to be 3.5 times more expensive than palivizumab, so that they will be able to tell you that there is a substantial saving in resources with the new drug (which would be true), and a reduction in pain and discomfort, but they will still be able to screw our health systems for as much profit as they possibly can! I used to think that drug pricing was based on development and production costs, with a profit margin added; how naive! Drug prices are based on the principle of AMAWCGAW (as much as we can we get away with, ©Barrington 2020), and I can’t see AzstraZeneca and Sanofi Pasteur deviating from that time-honoured principle.
I would love to be proved wrong.
Very interesting anaylsis and opinion. I find it disappointing to contemplate that there probably isn’t any need for nirsevimab to be developed at all. You could argue that it would have been a better use of resources to conduct more research on why the uptake of palivizumab is not optimised. Rather than spending all that money on developing a new drug, we could have used that money to fund a much more effective immunisation programme.
I would imagine if you interviewed parents, you’d find the main barrier is having both the vaccine, someone to administer it, and the infant, in the same location at the same time. Something easily fixable with an intervention like a nurse/pharmacist/medic who could travel to the family home to administer.
But for some reason, taking that approach is not really given a thought in the UK. Instead, as clinicians, we are left to try and uphold the conditions (i.e. the RCT protocol) in which the medicine was licensed, but without nearly enough resource to try and achieve this. I also would not be surprised to find the average course to be 3.5 doses (…some of my audit work has shown this).
Exciting new development! Before we do the math and make a decision to switch – as alluded to in your last paragraph, Keith – and given the 1st response to your blog, would we first need a pragmatic comparative effectiveness trial, nirsevimab vs. palivizumab, either head to head or cluster randomized, with the outcome that will be driving decisions to be measured: health system resource utilization (to be quantified across different systems and jurisdictions)? The palivizumab-evidence is old, and its cost-effectiveness was much debated a the time.
AMAWCGAW money rules. And even thought Palivizumab is used worldwide for years the price doesn t seem to go down .