Activity Transcript

Andrew Ustianowski, MBBS, FRCP, PhD: Hello, I'm Andrew Ustianowski and I'm a consultant in infectious diseases based in Manchester in the UK. Welcome to this program entitled "COVID-19 Vaccination Guidelines, Guidance and Impact of Immunization". Joining me today is Paolo Bonanni, who is professor of hygiene and public health and director of the Department of Health Sciences at the University of Florence in Italy. Welcome, Paolo.

So in this program, we're going to be discussing several things. We're going to touch on the current status of the COVID-19 pandemic, particularly focusing on the variants that are circulating, but also on those who are thought to be still at risk of severe disease and hospitalization. We're going to be looking at the impact of vaccination against COVID-19 and the rationale for booster doses. And explore who remains unvaccinated or has lack of protection despite vaccination and why. And finally, what are the current and future needs in terms of COVID-19 vaccination?

So, I'll start with a brief overview of where things currently stand with the pandemic. Here, we've got a graphic showing really that we've gone from the Wuhan or the wild-type strain through various variants, alpha, beta, delta, omicron. And this is quite a complex diagram showing where these different variants of concern have originated from. And the point I'd like to make is that unlike certain other diseases where a new variant really comes from the circulating present variants, at least when we look at alpha, beta, delta, and omicron, they've really derived from an earlier lineage, almost from the wild-type strain. And this means that predicting what the next variant of concern will be is actually very difficult. Things have been slightly different, however, with omicron. Within omicron, we've seen evolution with some quasi variants coming through with different susceptibility to immune based therapies such as vaccination and monoclonal antibodies and different infectivity.

So who's still at risk of severe disease and hospitalization? Well, the answer is we're not entirely sure. Now that we have a largely vaccinated or immune from natural infection population, things are a little bit different. But I think there's general agreement that immunocompromised individuals are still at more risk of severe disease. So that particularly is the stem cell and the solid organ transplant recipients, those receiving B-cell-ablative therapies, leukemias, lymphomas, and perhaps people who are on steroids, biological therapies, chemotherapy, and radiotherapy. That depends on what dose, what product and over what period of time. We were initially worried about people with HIV and AIDS, but reassuringly those that have a controlled virus on antiretrovirals and a good CD4 count don't seem to be at significantly greater risk than the general population.

And then we have those people with comorbidities spotted very early in the pandemic as having a relationship with more severe disease. And that's cardiovascular and lung disease, kidney, liver disease, neurological conditions, diabetes, and obesity particularly. But also, syndromes such as Downs syndrome, sickle cell disease, etc. And if we look more broadly, one of the main risk factors is actually being more elderly. But pregnant women and those unvaccinated or without protection from vaccines are at significant risk. So Paolo, can you tell us about the impact of COVID-19 vaccination?

Paolo Bonanni, MD: I would like to stress this concept of the impact that the vaccine had on mortality, highlighting an interesting study that was published in Lancet Infectious Disease last June by Oliver Watson and colleagues. It shows on the left part of the slide the actual number of deaths between December 2020 and 2021, so in 1 year. Under the black line and with the columns is the number of deaths that would have occurred without the vaccination. And we can see the daily number of deaths and overall, if we consider the excess mortality that was avoided thanks to vaccination, the actual number is 19.8 million deaths averted. Which is an amazing number of deaths that was avoided, thanks to vaccination.

In the right part of the graph, we see the situation in different geographical areas according to the level of income. So, again, high-income, middle-income and low-income countries. And here you can see that of course we could have that much more relevant results if we could have also reached high coverage in low-income countries that we have to reach in the near future.

And in another recent study, we can see the impact of different levels of coverage with vaccination. If we have 0% to 9% coverage, the impact on mortality is not so relevant. But if you reach 70% coverage in the population with at least 2 doses, you have an 80% decrease in mortality. And also the incidence is going the same way with original variants. Of course, there is a difference in the most recent variants because as a matter of fact, when we had the emergence of the delta variant, we saw a reduced neutralization against the new variants, reduced vaccine effectiveness against symptomatic disease, but we kept a very high coverage and protection against hospitalization. And that's from 92% to 97%, thanks to cellular immunity which is much more preserved than neutralization with antibodies.

And if you look at the decrease in neutralization against the latest variant, which is omicron, for all vaccines we see a 33 to 44 fold reduction compared with the ancestral strain, Wuhan. And this is true for all vaccines, but it's true also for natural infection as you can see in the left part of the slide. Which means that we are not as protected as in the beginning against symptomatic infection and asymptomatic infection.

But nevertheless, there is a recent paper from Young, published in JAMA, showing that the duration of virus shedding is reduced by vaccination, also with the most more recent variants. And secondary transmission was significantly less common in vaccinated people with breakthrough infection so, who manifested with COVID-19 infection, compared with those who were not vaccinated. So the difference was 7% vs 26%, a highly significant difference. And a viable virus in cell culture was detected for a notably longer duration in partially vaccinated subjects, 8 days after symptom onset or the unvaccinated 10 days after symptom onset, compared to people who were fully vaccinated, who had the viable virus in cell culture only for 4 days after symptom onset.

So what we can say and summarize in the end is that COVID-19 is evolving to be more transmissible with the new variants that are emerging. BA.2.12.1 and BA.4 And BA.5 exhibit higher transmissibility versus the BA.2 omicron variant. But we can also say that data so far are largely drawn from in vitro studies and it's difficult to obtain large scale clinical data, that we will probably get in the near future. So, Andrew, it's back to you.

Dr Ustianowski: Great. Well, thank you so much, Paolo. So, obviously the primary series of vaccination has a significant impact, but what's the rationale for booster vaccinations? Well, I think there are 2 sides to this. The first is waning immunity, which you touched on. So we know in natural coronavirus infections in prototype vaccines for other coronavirus, but also for SARS-CoV2, that whether vaccine induced or natural infection induced immunity, we don't see this prolonged. Over a period of weeks to months, we see a drop particularly in the neutralizing antibodies. Now, it may well be that the T-cell response, which are important to prevent against hospitalization and severe disease, persists for longer. But, undoubtedly, this is a disease area where we don't expect routine vaccination to result in long lasting immunity. So what factors are affecting this waning immune response? Well, the first thing we can consider is how high does the immune response come to begin with?

And actually by giving further doses, you may increase the immunity you start off with. Obviously, the longer since your last vaccine, the more waning would have been possible. But also if your immune system is impacting on your response to vaccination, for instance, your general immune status being elderly or having comorbidities, you'll start off at a lower level to begin with.

Now, we've got plenty of data explaining this, and here is an example in the elderly on vaccine efficacy, the extra benefit of having boosters. So, I hope you can see that when you've had primary vaccination, if you don't have a booster, your effectiveness drops down compared to those individuals who then go on and get a booster, either heterologous boosting or homologous boosting.

And let's touch on the immunocompromised individuals again. So we've already briefly discussed that seroconversion rates after COVID-19 vaccination are decreased. Lowest in organ transplant recipients, those on B-cell-ablative therapy, but also hematological cancers and some immune mediated disorders. A second vaccine dose has consistently been shown to improve the seroconversion or the neutralizing antibody titres, though the incremental increase tends to be less than in the otherwise thought to be healthy population. So in a lot of areas, immunocompromised individuals have been offered extra booster vaccinations.

And then, the separate reason to actually want a booster is to do with new variants. So, we fully expect new variants to develop. Now, these variants which arise may not be optimally protected against by the vaccines that we've already rolled out. And therefore, there will be a need for new tailored boosters for these variants. And we'll touch on this very briefly in a little while. So recommendations for booster doses vary between countries. Paolo, can you tell me about the recommendations in Italy?

Dr Bonanni: Of course, Andrew, the recommendations for booster doses for the fourth dose in Italy are for the following categories of subjects, provided that at least 120 days have passed since the first booster or since the last infection following the booster. And so, the fourth booster is recommended for subjects as aged more than 60 years, for subjects with comorbidities, aged over 12. But we also want to protect workers and guests of nursing homes, and healthcare workers, which are particularly at risk for the transmission of COVID-19 disease. And the last category is that of pregnant women, which is also under particular attention from the health authorities. If we look at the recommendation for the first booster dose or the fourth booster dose, this was recommended to the whole population aged over 12 from January fifth, 2020. So we aimed at covering with the third dose, all the population over 12 years of age. And I will go back to you, Andrew, to highlight what are the recommendations in the UK.

Dr Ustianowski: Well, thanks very much. Some similarities, some differences. So in the UK, anybody over the age of 16 can have a booster after their primary course of vaccinations. And individuals over the age of 12 if they have a health condition or a weakened immune response, or indeed live with someone who has a weakened immune response, can have a booster. Those people who are immunosuppressed, have had a booster in the early part of this year, an extra booster on top of this. And at present, we are rolling out our seasonal booster program, which currently is those aged over 50, pregnant, aged over 5, if they have a high risk themselves or live with someone at higher risk. And if you are a carer or if you work in a care home or in a healthcare setting. So let's briefly discuss the rate of uptake of COVID-19 vaccines and who remains unvaccinated. Over to you, Paolo.

Dr Bonanni: Yes, thank you. So we can see here, some selected countries and the level of coverage that they reached with the 2 doses or with partial vaccination with only 1 dose. And there are countries who perform very well. Portugal, is probably the top country in Europe. Italy performed well with 81% coverage with 2 doses and 86% with at least 1 dose, but France also performed well. The United Kingdom, a little bit less, but not so bad. And there are countries where coverage was a little bit lower like Poland and Hungary where we have to reach a higher coverage in order to protect the whole population.

And so, Andrew, there are also some particular reasons why some people remain unvaccinated. And I would like to ask you to highlight these reasons based on some of the data in the literature.

Dr Ustianowski: Well, there's a lot of literature and there's a lot of data, but there's also a lot of reasons why an individual or a group of individuals may choose not to be vaccinated. I've chosen just one bit, which I thought was interesting because actually it's looking at social media posts in Germany and the reasons highlighted for not receiving vaccination. And I'll just point out that the majority were health concerns, information deficits, systemic mistrust or a low perceived benefit or a low subjective risk of COVID-19. And so, I think the important lesson here is how vitally important it is to communicate effectively with the public and various groups within our public regarding the benefits of vaccination. And we may get a benefit, if we do it really well, of decreasing systemic mistrust.

In the last part of the discussion though, I'd like to look to the future. Paolo, where do you think we'll be in 2 to 3 years' time? And what do we need in terms of vaccination and vaccines?

Dr Bonanni: Oh, this is a very intriguing question, Andrew, and also difficult to reply. It's really not easy to forecast future vaccination needs. And then these needs will strongly depend on the epidemiological evolution of COVID-19 in the next years, but also from the achievement of high vaccination coverage with at least 2 doses in all countries, as we said in the beginning of this discussion. If we could have 70% of the world population immunized in a short time, we would probably see a move towards a milder endemic situation. This is an agreement among experts who forecast this decrease in the importance of COVID-19. But all the same groups who need boosters during and after this transition to endemic disease would be as outlined before: the immunocompromised, those affected by chronic diseases and, probably, also the general population would probably need some booster doses from time to time.

We don't exactly know at this time, every 1 or 2 years, or different timing. The boosters should be adapted to the new variants which will become predominant in the near future. But if we have not so much coverage, especially in the low and the middle income countries, we could see a more serious scenario with possible emergence of waning, variants of concern and possible periodical resurgence of epidemics. So we needed to cover more people who live in middle and low income countries, also to preserve the health of those who live in the high income countries. And I would like to go back to you, Andrew, for the final considerations.

Dr Ustianowski: Yes, well, I agree with all your points. I think it's important to say that the vaccines we use in the future may be different. So we're now moving into an area in some settings of using bivalent vaccines, including the wild-type strain and a more recent strain just to increase that breadth, but also the potential coverage of variants of concern. We have mucosal vaccines, inhaled, oral, intranasal, etc, T-cell vaccines or vaccines focusing particularly on T-cell responses for the reasons we alluded to earlier on. And adaptations of our existing technology, for instance, self-amplifying mRNA vaccines.

So I'd now like to conclude by highlighting, the key messages from our discussion. So, COVID-19 is here to stay. We will get new variants that come through, and those variants may be different, they may be more severe, they may be milder. They'll almost certainly have a degree of immune escape or otherwise increased transmissibility.

Vaccines have saved huge numbers of lives and vaccines are still our main way of controlling things. But we'll have to adapt. We will need booster vaccines in segments of our population and probably our population overall. We need to keep aware of the variants that come through and we need to particularly focus on who remains at risk within our populations. Having that global perspective is also really important, but we've got a distance to go. But I'm pleased to say, we've got a lot of things up our sleeves to help improve things. New vaccines, we're better at deploying vaccines, etc. So I'm optimistic about the future.

I'd like to thank you, Paolo, for such a great discussion and thank you the audience for watching. Please continue on and answer the questions that follow and complete the evaluation. Thank you.

This transcript has not been copyedited.