Not if, but when: Pandemic preparedness is crucial

On Wednesday 14th August, the World Health Organization (WHO) declared that the rapidly emerging mpox outbreak in Africa had become a public health emergency of international concern (PHEIC). By Thursday 15th August, the disease had reached Sweden – the first case of the severe variant outside of Africa.

According to the WHO, mpox (formerly known as monkeypox) is a viral illness caused by the monkeypox virus, a species of the genus Orthopoxvirus. Two different clades exist: clade I and clade II. Common symptoms of mpox are a skin rash or mucosal lesions which can last two to four weeks accompanied by fever, headache, muscle aches, back pain, low energy, and swollen lymph nodes. Mpox can be transmitted to humans through physical contact with someone who is infectious, with contaminated materials, or with infected animals.

The WHO’s PHEIC designation follows the rapid recent transmission of a more severe and contagious strain of mpox known as the clade Ib strain, which has the potential to spread globally in the months ahead. To learn more about the WHO’s declaration, and how a potential global outbreak can best be prepared for, pharmaphorum spoke with Dr Jay Varma, chief medical officer at SIGA Technologies – the developer of smallpox treatment TPOXX (tecovirimat) – and a leading expert in mpox epidemiology and public health.

History repeating itself

Following the global epidemic of mpox in 2022, there were extensive investigations, the results of which indicated that, as far back as 2016 or 2017, an outbreak might have begun in Nigeria, evidence showing an undetected transmission of mpox, primarily among men who have sex with men.

“So, essentially what you had is an outbreak that was uncontrolled, that eventually spread around the world,” said Dr Varma. “And that's a story that we've seen time and time again for other infectious diseases, whether it's Ebola or COVID. That brings us to 2024, and what we've seen is that, in the Democratic Republic of Congo (DRC), there has been a large and growing outbreak of mpox over the past several years; more recently, there has been the documentation of transmission between patients living in the DRC to those living in bordering countries, including Burundi, Uganda, and Kenya, and the other concerning feature is that those cases were almost certainly transmitted through sexual transmission.”

However, what's changed in the DRC compared to the global epidemic of only a couple of years ago is it's not limited to sex among men who have sex with men, but also involves people visiting commercial sex workers as well, Dr Varma noted.

“We know that commercial sex work is an important way in which STIs can cause huge epidemics,” commented Dr Varma. “It's exactly one of the ways in which HIV became a huge problem in southern Africa.”

Nonetheless, the Financial Times reported today that “two-fifths of cases in the DRC are in children under the age of five”, according to comment from Brian Ferguson, a professor of immunology at the University of Cambridge.

The WHO’s PHEIC, then, is a very much proactive measure, raising awareness across the entire spectrum of entities, given its decentralised nature – every single office globally will need to act. Indeed, the Africa Centers for Disease Control and Prevention (ACDCP) earlier advised that the continent will need two million vaccines doses by the end of 2025 to help control the outbreak, and the WHO last week instigated a process for emergency rollout of vaccines in countries without national approval, potentially helping to accelerate availability and enable GAVI and charitable bodies to procure vaccines.

The WHO’s declaration mobilises the ecosystem into awareness and action, for the protection of public health, including industry’s utilisation of available technologies to develop vaccines. For, at its core, the message of the WHO’s declaration is to vaccinate. Yet, vaccination is not a panacea; rather, early screening for relevant STIs is.

The clade Ib mpox strain

While the basic presentation of this infectious disease remains the same, the means by which it is transmitted has shifted slightly in the clade Ib variant – and it’s all too clear that this particular epidemic needs aggressive control.

“After you get infected, which can come through any form of close person-to-person contact – sex is the most efficient way to spread it, but it could be spread through other forms of skin-to-skin contact – there is a period of about, on average, seven days where you don't have any symptoms at all,” explained Dr Varma. “[Then,] patients often develop a fever and chills, a general feeling of being unwell, and can have swelling of their lymph nodes in different parts of the body. That is usually followed fairly quickly by the development of bumps on your skin. These look like small bumps, almost a little bit like a wart or something […] somebody might be familiar with, except smoother on their surface, and they could be quite painful to the touch.”

What is different with clade Ib is that, as opposed to an average of five to 20 bumps, the data from Africa is showing that patients infected with clade Ib get possibly hundreds across their entire body. This is far different from the strain that reached the US in 2022.

“If you are a person with an ‘intact’ immune system, [you’re] alright […] But with this virus strain, we know that the death rate can be much higher,” stated Dr Varma. “There's a lot of discussion and debate about the numbers behind that, but we're looking at somewhere on the range of maybe between 1% to 5% of patients who get infected might have a risk of death, and that's obviously higher if you have one of these immune- suppressing conditions like uncontrolled HIV infection.”

Available vaccines and a treatment for mpox

There are currently two vaccines for mpox available in the US: ACAM-3000 and JYNNEOS. However, in terms of treatments that are available, there is really currently only one antiviral drug: SIGA’s tecovirimat.

Indeed, yesterday, 15th August, The National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID) announced topline results from a preliminary analysis of the PALM 007 (Tecovirimat for Treatment of Monkeypox Virus) clinical trial. The NIAID reported, however, that the study did not meet its primary endpoint of a statistically significant improvement in time to lesion resolution within 28 days post-randomisation for patients in the DRC with mpox, who were administered SIGA’s tecovirimat, a highly targeted antiviral treatment, versus placebo. 

The PALM 007 study was part of a globally coordinated initiative to address the 2022 mpox outbreak occurring in the DRC and around the world, designed with important humanitarian considerations, such as allowing patients at varying stages of disease, age, health, among other factors, to participate in the trial. So it was that, to ensure study data could be collected accurately and that patients had access to food, all patients in the study were hospitalised for the duration of treatment, receiving a level of care unavailable to most mpox patients in real-world situations. And this is believed to have resulted in the one promising finding from the trial was: that the mortality rate for enrolled subjects was 1.7% – less than half the 3.6% rate reported among DRC cases overall.

Tecovirimat, known as TPOXX in the US, has not been approved for use for mpox by the US FDA. 

“It's only available in the United States through an expanded access experimental programme through CDC or through a clinical research study sponsored by the National Institutes of Health outside of the United States,” said Dr Varma. “However, it is approved for the treatment of mpox in the UK and in the European Union […] Our company was primarily involved in providing the drug and placebo and providing some scientific guidance for it, but [PALM 007] was fundamentally a research study done by the National Institute of Health in collaboration with IRB, which is a very large research institute in the Congo.”

The criticality of pandemic preparedness

In the broader scheme of global safety when it comes to potential future pandemics, Dr Varma was clear that awareness – as learned from the experience of COVID-19 – leads to important behaviour change, and that lesson should not be forgotten.

“What the general public and elected officials are learning is the same thing that those of us who have been working on infectious diseases for a long time have been sounding the alarm about: we live in a world that is closely connected, so a disease outbreak anywhere is a disease risk everywhere, and […] just as we worry about physical security from terrorism or from a foreign government waging war, we need to also be thinking about the risks of diseases spreading across borders. This is a lesson that keeps coming up: it’s a call to all of us to take our health security as seriously as we take our physical security.”

On this same topic, in late June, pharmaphorum spoke with Dr Kate Broderick, PhD, chief innovation officer at Maravai LifeSciences, who has been a pioneer for more than 15 years in the battle against rare and infectious diseases. Currently, she leads TriLink’s team of more than 300 to discover next-generation tech in mRNA therapeutics, aiming to get critical drugs and vaccines to the world more cheaply, quickly, and safely.

Dr Broderick’s discussion focused on another infectious disease: a wave of avian flu that had seen the first cow-to-human transmission of the virus on record, and left a man in Mexico dead in early June, with CSL Seqirus agreeing to provide 665,000 doses of its bird flu vaccine to the European Commission as part of the EU’s efforts to prepare for a potential outbreak of the disease shortly after, and the US government signing a $176 million deal with Moderna to develop an mRNA-based pandemic influenza vaccine by early July, as reports emerged of a fifth human case of H5N1 flu linked to ongoing outbreaks in poultry and dairy cows. As was all too well learned during the COVID-19 pandemic, such unprecedented human infection should never be ignored, as it can beyond the obvious risk of mortality bring severe disruption to urgent medical needs, routine healthcare, and society at large.

As a trusted industry leader, Dr Broderick herself was invited to the WHO meetings for the COVID-19 global pandemic response to share vaccine development updates, and she continues to serve as a principal investigator for a variety of grants and awards from government and non-profit organisations, such as the NIH and the Coalition for Epidemic Preparedness Innovations (CEPI).

Both Drs Varma and Broderick independently repeated the same warning: it is not a matter of if, but when a future pandemic will occur.

Avian flu and red flags

When it comes to determining what type of pandemic that might be, most in the infectious disease space long-assumed it would be another flu strain – then, COVID-19 came along.

“The fact that COVID kind of threw us a curveball […], and came up with a virus that we hadn't really expected, doesn't negate the fact that we're overdue for a flu pandemic,” stated Dr Broderick. "And so, everybody in this field has really been keeping an eye on the feedback that we're seeing in regards to the avian flu […] The fact that that's now hopping so readily into mammals, I think, really should be a major red flag for us: the fact that it's made that really fairly significant jump from avian-centred to mammalian species really is quite concerning and tells us that those mutations are occurring. And certainly, when you're looking at the genetic data, the sequence data around this particular virus species, we're seeing the mutation rates are higher than what we saw with COVID – which, again, should really be quite a red flag for us.”

The potential of mRNA vaccines 

Dr Broderick has spent much of her career looking at developing DNA-based vaccine and medicine approaches, utterly passionate about the infectious disease space. And now?

“What we are trying to see is how can we utilise our technologies that we've developed to help developers make their vaccines or medicines more efficient, more effective, aimed at treating the particular disease indication. We don't develop those products ourselves, we partner with developers to help give them the tools to make their products even more successful,” explained Dr Broderick. 

“Something we're particularly proud of is the fact that during COVID we were chosen as the capping technology for the Pfizer BioNTech vaccine […], a paradigm-shifting vaccine,” she continued.

It is off the back of this success that Dr Broderick and her team are looking for future applications of their technology. 

“On the heels of the amazing success of RNA vaccines within the global COVID pandemic, it makes rational sense that in the circumstances that we're seeing today unfolding in front of us, in regards to the avian flu, that an ordinary option would be a really optimal solution, to at least be tried in this setting,” she explained. “And I think you can see a lot of evidence of companies, academic institutions, all really leveraging the power of [these] vaccines to potentially combat the threat of avian flu.”

In terms of not leaving it to a matter of if, but when, then, it seems industry has its eyes and ears very much open, preparing determinedly for the approach of a broad spectrum of future pandemics. 

Feature image by artistlike from Pixabay
 

About the interviewees

Dr Jay K. Varma serves as the executive vice president and chief medical officer of SIGA Technologies. He was appointed to this role in September 2023. He has also served as a director since November 2022. Dr Varma was previously a professor of population health sciences and director of the Cornell Center for Pandemic Prevention and Response at Weill Cornell Medicine. He is an expert on the prevention and control of diseases, having led epidemic responses, developed global and national policies, and led large-scale programmes that have saved many lives in China, Southeast Asia, Africa, and the United States. From 2001 to 2021, he worked for the US Centers for Disease Control and Prevention with postings in Atlanta, Thailand, China, Ethiopia, and New York City. From 2020 to 2021, Dr Varma served as the principal scientific spokesperson and architect for New York City’s COVID-19 pandemic response. In September 2021, he joined Weill Cornell Medicine to conduct research, training, and programmes on public health and direct a new centre focused on pandemic prevention, preparedness, and response. Dr Varma graduated with highest honours from Harvard University for his undergraduate education, and completed medical school, internal medicine residency, and chief residency at the University of California, San Diego School of Medicine.

Dr Kate Broderick, PhD, is chief innovation officer at Maravai LifeSciences. She leverages more than 20 years of life sciences experience, with over 15 years in research and development as the head of Maravai’s newly established Science and Innovation Office. A recognised expert in vaccine and nucleic acid technology, Dr Broderick has led global teams and collaborated with industry, academic, and government partners to develop vaccines for a wide range of infectious diseases, including Ebola, MERS, Zika, HIV, Lassa fever, and COVID-19. Before joining Maravai in 2022, Dr Broderick held roles of increasing responsibility at Inovio Pharmaceuticals, most recently as senior vice president of R&D. Dr Broderick received her PhD from the University of Glasgow in Scotland and completed post-doctoral research at the University of California, San Diego.