LIV-TB is a cross-campus collaboration between the Liverpool School of Tropical Medicine and the University of Liverpool. In the following post, Dr Tom Wingfield talks about the current TB Pandemic. 

It is the worst of times. We are facing a pandemic.

A quarter of the world’s population is estimated to be infected. By the end of 2020, it is likely that 10 million people will have fallen ill, three million will not have been tested and treated, and over 1 million, mostly vulnerable people, will die.

This pandemic is not caused by the novel coronavirus, SARS-CoV-2, which leads to COVID-19.

It is caused by tuberculosis (TB).

Yesterday, on World TB Day 2020, and amid this unprecedented outbreak, we at LIV-TB and others think it is vital to compare and contrast the TB and COVID-19 pandemics - one old, one new - to remind ourselves why it’s still time to end TB. We have written a related comment that has been published here in Lancet Respiratory Medicine. 

So what is a pandemic? A pandemic is defined as a disease that spreads over a whole country or the whole world. TB and COVID-19 both fit this definition, affecting people across all six continents. No country is TB free and COVID-19 has now reached more than 180 of the nearly 200 countries on the planet.

There are striking similarities between the two pandemics. Both are a huge cause of illness and death around the world. TB is the single biggest infectious diseases killer, ending the lives of 1.2 million people in 2018. This is more than HIV and malaria combined. COVID-19 has infected nearly 250,000 people and caused nearly 10,000 deaths in the first quarter of 2020 alone. Both cause symptoms of fever, cough and shortness of breath. In countries with escalating COVID-19 cases, this is likely to mean that people with TB presenting to clinics and hospitals may go unrecognised or misdiagnosed. A similar pattern emerged in West Africa when cases of malaria were missed during the Ebola outbreak. Another similarity is that those at higher risk of more severe TB and COVID-19 disease and outcomes are older people and those with chronic illnesses. And, as we are discovering for COVID-19, both diseases lead to significant social impact including stigma, discrimination, and isolation; and economic impact related to country productivity losses and catastrophic costs to individuals and households.

There are also stark differences, the first being time. TB has accompanied us for thousands of years even being found in Egyptian mummies. SARS-CoV-2, on the other hand, is a new coronavirus that has spread rapidly around the world since December 2019. TB, previously known as consumption or The White Plague, is used to being labelled a pandemic. This is the first COVID-19 pandemic humankind has ever seen. Second, most children with COVID-19 will have only mild symptoms. The same cannot be said for TB, which in 2018 killed one in five of the 1.1 million children who became ill with TB. Finally, over 90% of TB cases and deaths occur in low- and middle-income countries. In contrast, Europe has been called the second epicentre of COVID-19 after China. Among other factors, this may explain why more funding and person-power will be put into the COVID-19 response in a year than TB has received in decades. However, modelling studies show us that vulnerable countries in sub-Saharan Africa and the Americas will soon be dealing with their own COVID-19 epidemics. We must all act together now to prevent a catastrophe.

There remain many unknowns. How TB and COVID-19 may interact is not understood. Put simply, TB rates could go up due to more people coughing due to COVID-19 who also have TB or go down due to self-isolation and quarantine. The risk factors for getting COVID-19 and having more severe disease appear to overlap and be similar to those for TB. These include being older, a smoker, male, having other chronic illnesses such as lung disease, and being poor. Undoubtedly, COVID-19, like TB, will be associated with the medical poverty trap, in which poorer people have a higher likelihood of infection, disease, and adverse outcomes. Also, unemployed people, informal or zero-hour contract workers, will experience further impoverishment, which increases TB risk.

The best of times would be to live in a COVID-19 and TB-free world. But this is a long way off and there is much to do. So, as we work together to control COVID-19, let's not forget the ongoing TB pandemic; still the biggest infectious diseases killer. We need to markedly increase funding to strengthen healthcare systems to address TB and to support research for a vaccine, better tests and medicines, equitable access to care, and socioeconomic support for people affected by TB. We need to continue to inform, advocate for, and empower local communities and to lobby governments and policymakers, to ensure that TB, as well as COVID-19, remain high on the global agenda. The lessons we have been taught by pandemics, old and new, are to be proactive, long-sighted, to plan ahead, and to not become complacent. 

Let's look forward to the best of times.

Read the full Lancet Respiratory Medicine article.

HIV-1 is the most common form of the HIV virus, and research to produce a vaccine is still ongoing. There is still considerable debate as to what is going to result in a successful HIV-1 vaccine, either preventative or therapeutic, and which strategies should be best employed to do so. It is still relatively unknown which combination of cellular or antibody immune responses are going to provide the optimal immunity required. The group of Bill Paxton and Georgios Pollakis are involved in two EU funded programmes analysing two different approaches, one is a T cell approach (a type of cell that forms the immune system) and the other is antibody (a protein produced by the immune system to neutralise pathogens).  

The ongoing H2020 funded European HIV-1 Vaccine Alliance programme includes HIV-1 infected individuals boosted with a substance designed to stimulate the immune system (an immunogen) aimed at heightening the response of T-cells to HIV-1. Participants receiving successful antiretroviral therapy will be vaccinated with a regime of a T-cell boosting immunogen after which they will be taken off therapy (treatment interruption) and time to viral rebound and to what extent measured. This will include a control arm to which time to viral rebound can be compared. During the vaccination protocol cellular immune responses will be measured by looking at HIV-1 viral loads. Furthermore, this study incorporates an arm receiving immunogen/placebo along with a special antibody (Vedolizumab) that has been linked with heightened immune response in the body’s mucosal linings. This study will identify whether therapeutic vaccination can provide benefit through increased elimination of HIV-1 infected cells and control of virus spreading through the blood. 

An EDCTP EU (bnAb-baby) funded proposal (started May 2019) is a vaccine proof of concept study looking to address whether neutralising antibodies have the potential to prevent HIV-1 infection in infants. A highly potent human neutralising antibody (VRC-007LS) will be administered to HIV-1 negative infants being breastfed by HIV-1 positive mothers. It is known that HIV-1 transmission can occur via this route even though mothers receive antiretroviral therapy. Breakthrough cases will be identified where virus being transmitted will be studied. These results will indicate whether high levels of circulatory antibodies have the potential to block HIV-1 transmission via this route of exposure and identify how potent they can be, whilst at the same time providing an indication of potential viral escape. How to induce such antibody responses would be the obvious aim stemming from these results.  

For vaccines to be successful they will likely have to induce immune responses that can clear HIV-1  ‘hiding’ in a resting or latent state in our own immune cells, or prevent the early establishment of such cells in newly infected individuals. Therefore, better understanding the cellular molecular environments that induce latency or support active viral replication is relevant to not only therapy but also vaccine success. Conversely, using therapeutic vaccines to activate T-cells may well enhance the possibility of HIV-1 transmission as well as virus replication in the case of therapeutic vaccines. Indeed, there are indications that the failure of the STEP vaccine trial, where more infections were reported among vaccine recipients than placebos, was due to cell activation and recruitment of cells to sites of exposure and thereby increased transmission. We are therefore actively involved in better understanding the molecular events that lead to increased infection and replication and are currently studying such mechanisms using cellular materials from the participants within our vaccine trials.

Certain types of parasite are known to change the immune response of their host through dampening or skewing T cell activation, to avoid the host immune system. Our most recent work (Mouser et.al. PLoS Pathogens e1007924, 5^th Sep 2019) demonstrates that two different antigens (kappa-5 and omega-1) from parasitic blood flukes can differentially effect HIV-1 interactions with the immune system. Kappa-5 has been shown to bind dendritic cells (part of the immune system) and can prevent viral capture and transfer, whilst omega-1 matures dendritic cells towards skewing T cells with a reduced capacity to support HIV-1 replication. These results indicate that co-pathogen interactions can alter HIV-1 transmission as well as subsequent viral replication. Vaccines that induce a similar immune response would therefore be advantageous as they would reduce the detrimental effects mentioned earlier, such as increased virus replication and transmission.

Hannah Williams is a Year 10 Work experience student spending a week learning about the research and communication activity of IGH. Here, she interviews IGH’s Professor Alan Radford to find out about his work and why it’s important.

Alan Radford is Professor of Veterinary Health Informatics at the University Of Liverpool. His job entails teaching vet students about viruses of relevance to animals and public health, and researching the use of big data to improve the health of animals and their owners.

As part of his work he leads SAVSNET (Small Animal Veterinary Surveillance Network), a project which uses electronic health data and which monitors the many diseases or infecting organisms tested for at veterinary diagnostic laboratories across the UK. The latter data can be analysed alongside real-time data recorded at the end of consultations from participating veterinary surgeons to monitor, for example, what antibiotics are being prescribed and whether antibiotic resistance is present in bacteria causing infections in animals. Moreover, SAVSNET helps to make information accessible for all, which will increase awareness and knowledge of diseases in the small animal population in the UK.

So how does research on big data helps us understand health in animals? Animals are a big part of our lives, recent statistics show 49% of adults in the UK own a pet. We also eat animals, as well as keeping them as companions, therefore their welfare is very important to us.

How does this benefit society? Not only do we want our animals to be happy and healthy but the health of animals can impact our health too. For example, if your dog has an illness there is a chance it may be passed onto you. To ensure this doesn’t happen, big data is a new way to better understand diseases that could be passed to humans and reduce these diseases.

What impact will this research have? The data collected shows all types of ill health in animals, therefore by looking at disease, SAVSNET can identify new ways to reduce the risk of diseases. An example of their work is chocolate poisoning in dogs. We all know that chocolate is poisonous to dogs, however do you know what time of the year chocolate poisoning most often occurs? Through using big data, they found Christmas was in fact the most common time of the year for chocolate poisoning in dogs to occur. Using this information, owners can be reminded to be careful where they leave chocolate lying around at Christmas and it enables vets to be aware they may have more cases of chocolate poisoning in dogs during the Christmas period.

What changes do you hope to see? SAVSNET will help to understand individual diseases, how common they are in vet practice, which animals are most likely to be affected, what are the best treatments and best ways to avoid disease in the small animal population of the UK.

Currently, Professor Alan Radford is working on a variety of diseases, as well as antibiotic use, tumours, rabbit dental disease and fleas infestations. When asked what made him want to become a researcher he said he never planned to; he wanted to be a vet, however after he got his veterinary degree, he discovered he wanted to create new knowledge and understand animals at a population level where he could have broad impact on improving animal health.

Finally, some of his favourite things about his job include working with people, being stretched to think of new ways of doing things, with every day different and that he is starting to see the research he is doing have an impact.   

Learning with the Experts - Liverpool Neuro ID Fellowship 2019

Sofia Valdoleiros is a Portuguese medical resident in Infectious Diseases and from January until March 2019, caried out a clinical and academical internship in Neurology, with a primary focus in Neurological Infection, with the Liverpool Brain Infections Group (LBIG), under Professor Solomon, also with Dr. Benedict Michael and Dr. Christine Burness.

The academical module took place at the Institute of Infection and Global Health (IGH), where I was so well received and involved in the activities by everyone. Along with the academical work I developed, I got to participate in the Liverpool Brain Infections Group meetings, which included the discussion of major research projects, such as Enceph-UK, and UK-ChiMES, major programmes on adult and paediatric encephalitis. I even heard from Professor Solomon himself on “How to write a winning grant”! I was given the opportunity to attend international meetings of ground-breaking multicentre projects, such as Brain Infections Global and ZikaPLAN, and what an honour it was to be able to take part in these meetings and actually meet world leaders in Neurological Infectious Diseases research!

Exciting activities seem to be always happening, such as these meetings or Neuroscience Day or open discussions about neuroscience research. I was sad my internship ended before some other events took place, such as the Big Infection Day or the Neurological Infectious Diseases Course, but these sure were “replaced” by other activities, such as the e-learning Neuro ID Course or teaching sessions with Dr. Benedict Michael, who invested a lot of time in discussing fascinating Neuro ID cases with me. 

The clinical module took place at the Walton Centre and the Royal Liverpool University Hospital. As a renowned neurosciences medical centre, at the Walton Centre it is possible to attend experts’ subspecialty Neurology Clinics, observe inpatients with neuro-infection and attend stimulating meetings, from Grand Rounds to Lectures from Neurology experts and teaching sessions, and MDT meetings such as Spinal Infection, Infection Control or Neuroradiology. At the Royal, I accompanied Dr. Burness, a Neurology consultant with a special interest in Neurological Infection, in observing referrals from the ID wards, and attended the Neuro ID Clinic, an innovative approach bringing together a Neurology consultant (specialized in Neurological Infection – Professor Solomon, Dr. Michael and Dr. Burness) and an ID consultant (Dr. Defres) in a multidisciplinary view of the patient. I was also given the opportunity to attend the Encephalitis MDT monthly meeting at the National Hospital for Neurology and Neurosurgery in London. I am so grateful for the opportunity to learn from these Neuro ID experts’ experience and for their valuable insights. It will certainly change my approach of the neuro infected patient in Portugal.

Overall, the major point I highlight is the amount of opportunities (to learn, to participate in) I was given in only 3 months. With so much and so interesting and versatile things to do, these 3 months just completely flew by. Thank you so much to everyone!