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Introduction To Infectious Diseases

Infectious diseases have plagued humans throughout history, and in fact have even shaped history on some occasions. The plagues of biblical times, the Black Death of the Middle Ages, and the "Spanish flu" pandemic of 1918 are but a few examples. The 1918 flu pandemic killed more than a half million people in the United States and up to 50 million people worldwide and is thought to have played a contributing role in ending World War I. 

Epidemics and pandemics have always had major social and economic impacts on affected populations, but in our current interconnected world, the impacts are truly global. This has been clearly demonstrated by the COVID-19 pandemic that began in 2020. Infections in one region can easily spread to another. Until the virus can be contained globally, a surge in cases in one area can cause a resurgence of cases in other areas around the world. 

Coronaviruses

Consider the SARS outbreak of early 2003. This epidemic demonstrated that new infectious diseases are just a plane trip away. The virus, SARS-CoV, which caused a severe, and sometimes fatal, respiratory illness emerged in China. Air travelers rapidly spread the disease to Canada, the United States, and Europe. Even though the SARS outbreak was relatively short-lived and geographically contained, the economic loss to Asian countries was estimated at $18 billion as fear inspired by the epidemic led to travel restrictions and the closing of schools, stores, factories, and airports. 

About a decade later, a new SARS-like virus emerged in Saudi Arabia. Named MERS-CoV, the virus causes Middle East respiratory syndrome, or MERS, a severe and often fatal respiratory disease. Infection occurs through direct contact with an infected animal (camel) or person. Even though MERS did not spread easily from person to person, the virus spread to 27 countries in the Middle East, Europe, Asia, and North America, including the United States.

The most recent coronavirus to emerge is named SARS-CoV-2. It causes the disease known as COVID-19. The effects of COVID-19 pandemic have been felt around the worldwide, with schools and businesses closing, travel restricted, and in some cases even limitations on people leaving their homes. The pandemic has caused major economic hardships, stressed healthcare systems, and impacted mental health. Disagreements within and between countries have arisen in how to respond to the crisis and how to allocate scarce supplies of drugs and vaccines. 

HIV/AIDS

The HIV/AIDS epidemic, particularly in sub-Saharan Africa, illustrates the economic and social impacts of a prolonged and widespread infection. The disproportionate loss of the most economically-productive individuals has reduced workforces and economic growth rates of affected countries, especially those with high infection rates. This impacts the health care, education, and political stability of these nations.

In southern Africa where the infection rate is highest, life expectancy plummeted in a mere decade from 62 years in 1990 -1995 to 48 years in 2000 – 2005. The existence of approximately 18 million children worldwide under that age of 18 that have been orphaned by HIV/AIDS highlights the impact of infectious diseases on families and societies.

Influenza

Historically, there have been about three to four influenza pandemics each century. The influenza virus is notable for its ability to change its genetic information. When a new version of the influenza virus arises that has either never circulated in the human population or has not circulated for a very long time (so that most people do not have immunity against the virus), a pandemic can occur. 

There were three influenza pandemics in the 20th century – the "Spanish" flu of 1918-19, the "Asian" flu of 1957-58, and the "Hong Kong" flu of 1968-69 – and one in the 21th century, so far – the 2009 H1N1 "swine flu" pandemic. 

Other influenza variants have emerged in recent decades including the avian H5N1 influenza (or "bird flu") in 2005 and the H7N9 virus in 2013. The H5N1 virus caused concern because it was so deadly (more than half of the cases were fatal), but it did not spread easily from person to person. Additional novel versions will continue to emerge. The greatest danger would come from a version of the flu virus that is very deadly but is also transmitted readily from one individual to another.

Research On Infectious Diseases Requires Better Coordination

This special supplement of Nature Medicine, directed at the topic of emerging infectious diseases, is very timely. Recent high-profile outbreaks have highlighted the global risk that infectious agents, both new and old, represent for society. The experience of severe acute respiratory syndrome (SARS) shows the risk posed by emerging infectious diseases, but also the power of strongly coordinated global surveillance and public health measures, coupled with scientific research, to keep infection under control1,2. Diseases such as drug-resistant malaria continue to be threats. There is a need to enhance global resources to investigate, detect and respond to emerging infections, and to appropriately coordinate and direct research efforts to meet the challenges presented by these diseases.

Despite the success of dealing with SARS, we have the historic examples of plague and the influenza outbreak of 1918 to inform us of how outbreaks can spread globally if they are not appropriately contained. We also have the recent experience of the human immunodeficiency virus/acquired immune deficiency syndrome pandemic as a constant reminder of how some diseases can emerge, not as an acute, self-regulating outbreak, but as diseases with chronic, long-lasting impact. One of the key elements of the successful containment of SARS was its early detection and identification within relatively strong health care systems and research environments, and the ability to mount a coordinated global response. Many of the challenges that we face in the area of emergent infections result from the fact that they frequently occur in poor, resource-constrained settings where it is more difficult to be prepared and to mount an effective response. In addition, many emergent infections and epidemics are not the results of 'new' diseases, but of the poor containment of well-understood diseases, such as drug-resistant malaria, drug-resistant Staphylococcus aureus and other infectious agents.

Although I will refer to many types of diseases, two related issues will permeate this commentary. First, there is a need to enhance global investment in both developed and developing countries to improve their capacities to research, detect and respond to emergent infections2,3,4. Second, there is a need to better coordinate and direct research to meet the challenges and threats posed by these infections. In contemplating these two issues, it is important to recognize the strong link between the research capabilities that countries have and their abilities to respond locally and nationally to the threat of disease5,6.

If we are to maintain global security against emergent infections, it is just as important to invest in and develop research expertise and capabilities in poorer countries, as in wealthier countries. Many poorer countries, of course, are unable to internally raise the resources necessary to meet their needs. In these cases, international and bilateral funding should be made available in a manner that facilitates local capacity building, local ownership of research and the local development of solutions and responses. Apart from the moral and equity-driven considerations that justify the provision of assistance to developing countries to increase their research and other capabilities to address emergent infections, there are also reasons of enlightened self-interest. Diseases do not recognize borders.

Research responses and priorities

The range and type of diseases covered within this supplement is both informative and illuminating. Within it, we move from influenza to SARS to flaviviruses to hemorrhagic fever viruses to drug-resistant bacteria and parasites. These diseases may emerge as 'new' epidemic or pandemic diseases for which we have limited pre-existing knowledge, or re-emerge even though they are 'old' and often well understood. In addition to these 'naturally occurring' diseases, we now also need to include possibilities of the 'intentional introduction' of infections. Smallpox, which represents one of the most notable public health successes of all time7, is often included in this discussion. Through major efforts of global scientific, human and organizational endeavor, this disease was removed from the planet as a health concern. To conceive of it being purposefully reintroduced is beyond comprehension, yet a potential reality.

In their article on a conceptual framework of public health surveillance and action and its application in health sector reform, McNabb et al.4 clearly show how health systems can link surveillance to action. They define two categories of public health action: acute (epidemic-type) and planned (management-type) responses. This concept helps to define a conceptual framework for surveillance and response to emergent infections (Fig. 1). From a research perspective, we must also classify diseases in a way that can assist in appropriate action-oriented research. This can be done by placing emergent diseases into three categories, each of which will require a different type of research response: (i) new emergent infections (ii) rare infections, which may re-emerge occasionally or be considered a biodefense threat, and (iii) common infections, which may increase in significance owing to issues such as social instability or resistance development.

Figure 1

Conceptual framework of public health surveillance and action (used with permission from ref. 4).

New emergent infections. For new emergent diseases, we require, first and foremost, strong surveillance and response systems with the capacity to rapidly identify the nature of any new disease. Within this context, the development of networks of research institutions and centers for disease control is imperative, as occurred during the SARS outbreak1,2. A major initial emphasis on the development of diagnostic techniques is often a high priority, coupled with the need to assess as early as possible if any existing interventions can also be used against the new disease. For example, the discovery that some anti-influenza drugs are active against avian flu allows for contingency plans to be developed in case of a future outbreak8. Equally important, lessons in case management need to be documented rapidly and made widely available.

Rare infections. For diseases that re-emerge occasionally (such as hemorrhagic fevers) or diseases that could be used as biological weapons (such as anthrax), there is a prime need for active surveillance and response systems to be put in place. But in these cases, research can be initiated in advance to develop tools (diagnostics, drugs and vaccines) so that they are available when an outbreak occurs. For biodefense, there is a strong public-sector, security-led imperative to develop such tools, which may be matched in certain cases by military investment9. For rare infections, however, the difficulty in undertaking human clinical trials to evaluate these tools makes it difficult to fully assess their efficacy. In the US there has recently been a huge influx of National Institutes of Health funds into biodefense-related research. But for diseases such as Ebola and other hemorrhagic fevers10 that arise occasionally and affect relatively marginalized populations, there is more difficulty in obtaining research funds. Even if funds are obtained, it often occurs subsequent to a major outbreak when the 'political' interest is at its highest, and it is extremely difficult to maintain those levels for long-term planning. Sustained long-term funding is usually a prerequisite to deliver practical research outputs.

Common infections. For bacterial and parasitic diseases, such as drug-resistant S. Aureus, tuberculosis and malaria, and for other, more widespread infectious diseases, such as dengue, there may already be considerable epidemiological monitoring in place. But even for common diseases such as malaria, there is additional need for surveillance, drug resistance monitoring and pharmacovigilance, especially in less-developed countries5,6. A feature for many, although not all, of these diseases, is that tools such as drugs may be available, and there is a research community in place with an interest in developing new and improved tools and methodologies to counter the disease. Once again, the diseases most associated with poverty, or that are more definitively seen as diseases of developing countries, tend to be underfunded, despite their huge global burdens. A classic example is African trypanosomiasis, or sleeping sickness, which emerges primarily in regions suffering social disruption and unrest, and which lacks affordable, safe and effective drugs and diagnostics. At the beginning of the twenty-first century, an arsenical agent remains a key intervention for the treatment of this disease.

In addressing the problems posed by the diseases mentioned above, it is important to think about the science behind the diseases and the need to generate new knowledge. But we also need to address how we, as a society, should organize science and research to develop improved tools and methodologies, both to prevent the re-emergence of disease and to deal with the emergence of disease once it has occurred. One of the fundamental constraints for dealing with many of the diseases under discussion is that they do not represent a substantial commercial market. The competitive pharmaceutical market approach that works in general for the development and production of new drugs, diagnostics and vaccines does not work for these diseases. The diseases must also be viewed within the context of national surveillance and control strategies. In many cases the resources available to support these systems is limited. Nevertheless, for the sustainable development of new tools and their optimal use, together with the development of appropriate methodologies and control strategies, it is important that research be carried out in a way that it can link to, and be adopted into, national control strategies and systems11.

In moving forward with this difficult research agenda for emergent infections, it is worth considering some of the learning experiences of research into tropical or neglected infectious diseases, including malaria, over recent years12,13,14,15. It has long been known that tools need to be developed for these indications, despite a limited market for new products and that there is a need to ultimately implement these tools in resource-poor health systems. This has led to the development and utilization by the Special Program for Research and Training in Tropical Diseases of comanaged partnerships, both to deliver new tools and to facilitate their subsequent implementation. Many successful products have been developed in partnership with the pharmaceutical industry, and this will be covered in more detail in the next paragraph. For the delivery and implementation of new tools and strategies, industry may remain involved, but it becomes increasingly important to engage in research with national and international programs associated with health and development. A recent example of such an approach has been the development of strategies for the management of malaria close to the home15. There may be lessons from the tropical disease research experience that can be applied to the other emergent infections, both through public-private partnership for product development and through broader research partnerships in countries.

One of the most significant developments that has occurred in the fight against neglected diseases has been the establishment of public-private partnerships for product development16,17,18. These partnerships operate on the principle that public sector investment and expertise needs to combine with industry investment and expertise to deliver products that neither sector is capable of, or willing to, develop by itself. For example, industry may focus on chemistry, formulations and preclinical and regulatory activities, whereas the public sector may focus on defining the type of product required and the clinical studies required for their development. This mode of operation and sharing of risk has become increasingly important as the costs of drug research and development have increased. It is now estimated that, for every new product that comes on to the market, the pharmaceutical industry has invested approximately $800 million. Even though resources of the public and private sectors are combined in partnerships, it is rare that companies make any substantive profit on the products in the area of neglected diseases. Much of the assistance is provided in a spirit of corporate social responsibility. Under appropriate agreements, the industrial partner normally undertakes to provide preferential pricing to the public sector in developing countries. In some cases the product may even be donated.

Starting in the late 1970s and early 1980s public-private partnerships were predominantly isolated, 'single-project' initiatives. In this regard, the Special Program for Research and Training in Tropical Diseases has worked with companies such as Novartis to develop multi-drug therapy for the treatment of leprosy, Merck to develop ivermectin for treatment of onchocerciasis, Aventis to develop intravenous eflornithine to treat African trypanosomiasis, Zentaris to develop miltefosine for leishmaniasis and GlaxoSmithKline to develop chlorproguanil-dapsone for malaria. Similarly, the Walter Read Army Institute of Research has worked with GlaxoSmithKline to develop halofantrine and with Roche to develop mefloquine, both drugs for the treatment of malaria. In the past five years, this concept of public-private partnership has expanded to include the establishment of new organizations focused on specific indications, such as malaria drugs (Medicines for Malaria Venture), malaria vaccines (Malaria Vaccines Initiative), tuberculosis drugs (Global Alliance for TB Drug Development), HIV vaccines (International AIDS Vaccines Initiative) and tuberculosis diagnostics (Foundation for Innovative New Diagnostics). Many of these organizations have established strong portfolios of projects, and it is anticipated they will start to deliver new products soon.

The principles of public-private partnership established through these activities might find application more broadly in the emergent infections area. In addition to the issues of developing products for diseases such as SARS and anthrax, it is also noteworthy that many companies are now pulling out of infectious disease research, including antibacterial research. This is because there are many safe and effective antibacterial drugs on the market and it is difficult to improve on them. To repay the cost of development, a successful antibacterial needs to be highly efficacious against multiple types of infection. Developing a new drug just to combat a specific type of drug-resistant bacteria is unlikely to provide adequate return on investment, even if the impact on public health, particularly on hospital infections, can be considerable. It may be that lessons in public-private partnership developed for the major neglected diseases of developing countries might find application for these specific types of 'orphan' indications in developed countries.

Linking research to sustainable capabilities and country-led intervention. It is widely accepted that building appropriate human resource and institutional capabilities in developing countries is essential for the sustainable delivery of public health control measures. There is less recognition of the importance of research capabilities for the development and implementation of sustainable methodologies and strategies into health systems in developing countries.

McNabb et al.4 described the link between capability strengthening, public health surveillance and action. To enhance national capabilities in selected countries, they initiated meetings at the regional and national levels to assess and reform surveillance and action systems so that local needs could drive the agenda. To meet the needs expressed for standardized assessments and reform, the authors designed a conceptual framework for surveillance and action that included both core and support activities. Actively managed surveillance addressing both acute (epidemic-type) and planned (management-type) responses was undertaken, enabled by support activities—communications, supervision, training and resource provision. The final public health model became a district-focused, action-oriented integration of core and support activities that could be readily evaluated and led to sustained capacity development through an empowerment strategy that transformed both the staff and the system. Within this approach, the development of enhanced laboratory capacities for monitoring and surveillance within national health systems was a prerequisite to effectively detect and combat emergent infections.

In a similar way, research that leads to the establishment of appropriate methodologies and strategies for disease detection and control must be linked to national health systems, institutions and personnel. This is necessary to provide appropriate legitimacy, local input and, ultimately, local endorsement of data and conclusions. One can view the linkage of use-inspired research to implementation and impact as a continuum of activity that develops from the establishment of basic knowledge, through tool development to the establishment of methodologies and strategies. Such a continuum can be organized in a way that bridges a research strategy to local capacity-building activities (Fig. 2).

Figure 2: Conceptual framework of research continuum interfacing with capacity building and knowledge management for the delivery of health impact.

The term 'capacity building' refers to the development of research capabilities in developing countries so that scientists and institutions in those countries can initiate, contribute to and address the health research issues facing their societies. The term 'knowledge management' refers to the analysis of current knowledge and research capabilities so that this analysis informs research strategies to address public health needs.

An excellent example of how the continuum of research can allow the transition from tool development to research associated with tool implementation in disease control, and therefore into health impact, is perhaps most clearly illustrated by onchocerciasis19. Early laboratory studies identified ivermectin, a veterinary product, as potentially active against Onchocerca volvulus, the causative agent of human onchocerciasis, or river blindness. A subsequent public-private partnership with Merck led to the development of the drug for human use and also to a generous drug-donation program by Merck. With the new drug available, methodologies still had to be worked out as to how the drug could be effectively distributed across many resource-poor and dispersed communities. Ultimately, locally empowered, community-directed treatment strategies were developed that proved to be more effective than externally managed strategies. Over a period of many years, this activity has substantially reduced onchocerciasis as a public health threat and has liberated many hectares of riverside land for agricultural use. The utility of community-directed treatment strategies is also being explored for other disease management interventions.

Health research systems. It is increasingly important to view health research as an integral component of health systems. Strengthening appropriately directed health research and relevant technologies can also strengthen health systems and help ensure appropriate knowledge levels and capacities. But if health research is to deliver on scientific promise, it is important that that there be focused, managed and coordinated research programs undertaken in addition to traditional 'investigator-led' research. Investigator-initiated research is excellent for enhancing our understanding of disease and providing innovative insights into potential new approaches to tackling disease. But to convert these ideas into realities it is normally necessary to create consortia of scientists that are well managed and work together under commonly agreed objectives.

It is such coordinated research that has delivered much of the genomic information that has been gathered over the last few years. It is such coordinated and managed team-based work that delivers new drugs, diagnostics and vaccines from the pharmaceutical industry and through public-private partnership. An increasing number of new organizations proactively manage a portfolio of drug- and vaccine-development projects16,18. In addition, broader, more ambitious collaborative efforts are being discussed, such as the global HIV vaccine enterprise proposed by Klausner et al.20.

From a scientist's perspective, there is a need to ensure that investigator-initiated research is closely integrated into these approaches so that innovation continues to be stimulated and nurtured. One of the major challenges to any health research system is to ensure an appropriate balance between investigator-initiated research on the one hand and 'use-inspired,' coordinated and managed research on the other.

Most of the examples of significantly coordinated and managed health research for strategic impact on emergent infectious diseases occur at the level of knowledge generation (such as genome sequences) and tool development (such as new drugs and diagnostics). There are increasing examples of coordinated, multicenter trials to impact on drug policy21,22. But there is a need for more significant and better coordinated research, aligned to health system needs, that can usefully inform national and international strategies and policies and lead to enhanced implementation in developing countries. It is incumbent upon the numerous research funding agencies and stakeholders, as well as individual scientists to ensure their research has impact to take the needs and stakeholdership of developing countries into account. There is a need to improve levels of international cooperation and coordination, both among agencies and with relevant national institutions.

As AI Agents Spread, So Do The Risks, Scholars Say

Xuanyu Han/Getty Images

We've known for some time now that AI models can be made to perform erratically using adversarial examples, or subtly crafted inputs that appear ordinary to humans.

For example, in the case of chatbots that handle both text and image inputs, scholars at Princeton University last year found they could input an image of a panda, subtly altered in ways imperceptible to humans but significant to the chatbot, and cause the chatbot to break its "guardrails."

"An aligned model can be compelled to heed a wide range of harmful instructions that it otherwise tends to refuse," the authors wrote, such as producing hate speech or giving tips for committing murder.

Also: The best AI chatbots

What would happen if such models, as they gain greater powers, interact with one another? Could they spread their malfunctioning between each other, like a virus? 

Yes, they can, and "exponentially," is the answer in a report this month from Xiangming Gu and his colleagues at the National University of Singapore and collaborating institutions. In the theoretical paper, Gu and his colleagues describe how they simulated what happens in a "multi-agent" environment of Visual Language Models, or VLAs, that have been given "agent" capabilities. 

By injecting a single chatbot with an altered image that can be stored in its memory, an attacker can watch the altered image spread through the automated interactions of the chatbots as they converse.

National University of Singapore

These agents can tap into databases, such as the increasingly popular "retrieval-augmented generation," or, RAG, which lets a VLA retrieve an image from a database. A popular example is named LLaVA, for "large language and vision assistant," developed by Microsoft with the help of scholars at The University of Wisconsin and Columbia University.

Gu simulated what happens when a single chatbot agent based on LLaVA, called "Agent Smith," injects an altered image into a chat with another LLaVA agent. The image can spread throughout the collection of chatbots, causing them all, after several rounds of chatting, to behave erratically.

"We present infectious jailbreak, a new jailbreaking paradigm developed for multi-agent environments," Gu and team wrote, "in which, analogous to the modeling of infectious diseases, an adversary need only jailbreak a single agent to infect (almost) all other agents exponentially fast."

Also: I asked Gemini and GPT-4 to explain deep learning AI, and Gemini won hands down

Here's how it works: The authors "injected" an image into Agent Smith by asking it to select from a library of images contained in an image album using RAG. They injected the chat history with harmful text, such as questions about how to commit murder. They then prompted the agent to ask another agent a question based on the image. The other agent was tasked with taking the image given to it by Agent Smith, and answering the question posed by Agent Smith.

After some time, the adversarial image prompted one agent to retrieve a harmful statement from the chat history and pose it as a question to the other agent. If the other agent responded with a harmful answer, then the adversarial image had done its job. 

Their approach is "infectious" because the same malicious, alerted image is being stored by each answering chatbot, so that the image propagates from one chatbot to the other, like a virus.

Also: The safety of OpenAI's GPT-4 gets lost in translation

Once the mechanics were in place, Gu and his team modeled how fast the tainted image spread among the agents by measuring how many produced a harmful question or answer, such as how to commit murder. 

The attack, of course, has an element of chance: once the altered, malicious image was injected into the system, the virus' spread depended on how often each chatbot retrieved the image and also asked a harmful question about that image. 

The authors compared their method to known methods of infecting multiple agents, such as a "sequential attack," where each pair of chatbots has to be attacked from a blank slate. Their "infectious" approach is superior: They find that they're able to spread the malicious image amongst the chatbots much faster. 

"The sequential jailbreak ideally manages to infect 1/8 of almost all agents cumulatively after 32 chat rounds, exhibiting a linear rate of infection," Gu and his team wrote. "Our method demonstrates efficacy, achieving infection of all agents at an exponential rate, markedly surpassing the baselines."

"…Without any further intervention from the adversary, the infection ratio […] reaches ∼100% exponentially fast after only 27 - 31 chat rounds, and all infected agents exhibit harmful behaviors," according to Gu and his team. 

From an attacker's point of view, the infectious route makes attacking systems of agents much easier. "To jailbreak almost all N agents in a multi-agent environment," Gu and his team wrote, "an infectious jailbreak method enables the adversary to incur a fixed cost for jailbreaking (only needing to initially jailbreak a fraction of agents […], and then waiting for a logarithmic amount of time with no further intervention."

Such a risk may seem far-fetched. Most human users are accustomed to working with a single chatbot. But Gu and his team warn that chatbot agents such as LLaVA, armed with memory retrieval, are being integrated into AI-infused infrastructure. 

Also: What to know about Mistral AI: The company behind the latest GPT-4 rival

"These MLLM [multi-modal large language model] agents are being integrated into robots or virtual assistants, granted memory banks and the ability to use tools, in line with the growing trend of deploying MLLM agents in manufacturing or daily life," Gu and his team wrote. 

There is hope for forestalling the infection, the authors wrote. Because there's an element of chance around whether a given chatbot agent retrieves the adversarial image in a given round of chat, infection can be stymied by reducing the chances that an agent spreads the malicious image.

"If a defense mechanism can more efficiently recover infected agents or lower down infection rate […] then this defense is provably to decrease the infection rate to zero […]" they wrote.

However, they also added, "How to design a practical defense for our infectious jailbreak method remains an open and urgent question."

Artificial Intelligence I asked Gemini and GPT-4 to explain deep learning AI, and Gemini won hands down How to use ChatGPT's file analysis capability (and what it can do for you) I tried Copilot Notebook: Microsoft's new AI tool offers two handy prompt features What to know about Mistral AI: The company behind the latest GPT-4 rival

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