Photo: Getty Images
Photo: Getty Images

ScienceJuly 29, 2020

Spread the word: The rules of contagion are more important than you think

Photo: Getty Images
Photo: Getty Images

The R number, the classic measure of how easily an infectious disease spreads, is how New Zealand crushed community transmission. But it’s also a clever guide to a much bigger picture, writes Jenny Nicholls.

Predicting how the global Covid-19 pandemic will progress can seem impossible, with graphs of cases from other countries beginning to look like blueprints for a rollercoaster. Where will it all end? Our best estimates come from epidemiologists, who use maligned techniques like “modelling” and “R” to help figure out what will happen next. 

Today most of us are reluctantly getting to grips with the “reproduction number” R – the classic measure of how easily an infectious disease spreads. All over the world, governments are beginning to use it as a sensor for trouble, like a sea of frowning Hollywood submarine captains tapping their gauges. 

The Rules of Contagion is a new book by 33-year-old London academic (and Twitter star – @AdamJKucharski) Adam Kucharski, an associate professor at the London School of Hygiene & Tropical Medicine. Kucharski is interested in the mathematical analysis of infectious disease outbreaks but despite this, it’s easy to like his book. He doesn’t rely on graphs and equations to explain R and herd immunity, but sympathetic tales of the men and women who figured all this stuff out.

If R is higher than one, an infected person can be expected to share their microbial guest with one or more others, and infections will tend to outpace recoveries. If R is below one, hurrah! Everyone can breathe more easily.

R, in other words, is elastic, an estimate depending on four factors that are tricky to measure: the length of time a person is infectious; the average number of people they interact with each day; the probability their contact will become infected; and the susceptibility of a population. 

Social inequality and living conditions affect some of these factors. Without cure, effective treatment or vaccine, really only one of these can be changed relatively easily in a privileged society. During the level four lockdown, our average daily contacts (number two in the list) dropped so dramatically that our Covid-19 “effective” R value dwindled to 0.35 – an astonishingly low figure. (This was estimated by the team from Te Pūnaha Matatini: the Centre for Complex Systems and Networks, hosted by the University of Auckland).

0.35! This R value is how we crushed community transmission – for now, at least.

Outside New Zealand, R values ranging from 1.5 to 6 have been reported for Covid-19, according to the same group, although others put it at 2.5. 

To help get your bearings, smallpox (now extinct “in the wild”) had an R of 4-6 (with a risk of death of about 30%, unless you were a baby, in which case it was higher). 

Chickenpox is even more infectious, with an R of 6-8. The R heavyweight is measles, one of the most infectious diseases on the planet. In an unvaccinated and susceptible community, one case can lead to 20 or more, on average. The New York Times records R values for measles ranging from 3.7 to 203.

Welcome to the world of mathematical modelling. 

It might sound messy, says Kucharski, but, “in essence, a model is just a simplification of the world, designed to help us understand what might happen in a given situation. Mechanistic models are particularly useful for questions that we can’t answer with experiments. If a health agency wants to know how effective their disease control strategy was, they can’t go back and rerun the same epidemic without it.” 

Although this book was written before the pandemic, it is a clever guide to a bigger picture – a much bigger picture. These “rules of contagion” can be applied to financial panics, epidemics of gang violence, the spread of ideas, or online misinformation. Anything, in fact, that can “go viral”.

Unlike the armchair scientists we meet online, in Kucharski’s world uncertainty isn’t a weakness – it’s a tool of the trade. “In outbreak analysis, the most significant moments aren’t the ones where we’re right,” he says. “It’s those moments when we realise we’ve been wrong. When something doesn’t look quite right: a pattern catches our eye, an exception breaks what we thought was the rule.” These are the moments, he says, “that allow us to unravel chains of transmission, searching for weak links, missing links and unusual links”.

Auckland University professor Shaun Hendy led the Te Pūnaha Matatini team that modelled scenarios for Covid-19 in New Zealand. “Kucharski has been one of the key international scientists in the Covid-19 response, putting his deep expertise to work, as well as communicating his work as he goes,” Hendy says. “He is well worth a follow on Twitter, if you want an informed cutting-edge perspective on the science of Covid-19.”

Give models a chance

It is easy to attack the projections made by a scientific model. Even renowned scientists like the epidemiologist Neil Ferguson from Imperial College, London, are accused of making “predictions” that don’t stack up. But models are often designed to show a range of scenarios. To understand the value of any model, it’s important to know the assumptions on which it was built. If you can, check the original paper before assuming the epidemiologist is a feckless dunderhead. You may well come away with a new respect for their methods and care, if not for their conclusion.

Bear in mind that a disputed number might be a projection of case numbers under a “no lockdown” scenario that never happened. If the model was an early one, it would have been built with the meagre data available in the first months of the pandemic. Countries collect data in different ways, even within their own borders. For instance, some US states count only “confirmed” Covid deaths, but not “probable” ones, making data collection across the country inconsistent. Epidemiologists, notes Kucharski, seldom have the luxury of a perfect dataset.

The increase in Covid-19 cases is exponential, so even a slight difference in assumptions can have a big effect on the end result. One way to experience this for yourself is to try Te Pūnaha Matatini’s Covid-19 Take Control, a simulator that anyone can use. The US website FiveThirtyEight has assembled 16 models published by scientists to illustrate possible trajectories of the pandemic’s US death toll. These show the assumptions underlying each model and how they lead to different estimates. The same website has a brilliant explainer on “why it’s so freaking hard to make a good Covid-19 model”.

Keep going!
Illustration: Toby Morris
Illustration: Toby Morris

ScienceJuly 28, 2020

Siouxsie Wiles & Toby Morris: The race for a Covid-19 vaccine, explained

Illustration: Toby Morris
Illustration: Toby Morris

Well over 150 vaccine candidates for Covid-19 are in development, and they take a myriad of forms. Siouxsie Wiles helps make sense of the different approaches, with illustration by Toby Morris.

For more Siouxsie-Toby collaborations, see here.

With the exciting news that two Covid-19 vaccine candidates (Oxford/AstraZeneca and CanSino Biological Inc/Beijing Institute of Biotechnology) have done well in early-phase human trials, here’s a quick guide to the different types of vaccines under development.

According to a recent analysis by the World Health Organisation, there are currently well over 150 vaccine candidates for Covid-19 being developed. About 140 of these are currently undergoing what is known as “preclinical” testing. This means they are still at the lab stage, perhaps getting as far as being tested to see if they work in animals. The more exciting news is that more than 20 candidates are already in various stages of being tested in people.

The different clinical trial phases

Before I explain a little more about the different Covid-19 vaccine candidates, here’s a very quick summary of the different stages of testing in people that they’ll need to go through.

A phase 1 clinical vaccine trial usually involves fewer than 100 healthy people. They will be given the experimental vaccine, perhaps at different doses, to find out if it is safe and whether there are any serious side effects. A phase 2 trial involves more people, again looking for common side effects, but also looking to see if people’s immune systems recognise it and mount a response. If they don’t then that’s the end of the road.

But if people do mount an immune response, then the candidate can move onto a phase 3 trial. Here the number of people vaccinated increases into the thousands to tens of thousands and we start to get information on whether the vaccine might actually work.

The different types of vaccines

There are three main approaches to making a vaccine. What makes them different is whether they use a whole virus or bacterium, just the parts of them that trigger our immune system, or just the genetic material that codes for the parts that trigger our immune system.

The whole microbe approach

The first way to make a vaccine is to take the offending virus or bacterium, or one very similar to it, and kill it using chemicals, heat, or radiation. This is what is known as a dead or inactivated vaccine. The advantages of this approach are that it’s well established technology that we know works in people – this is the way the flu and polio vaccines are made – and vaccines can be manufactured on a reasonable scale. The downsides, though, are that it requires special laboratory facilities to grow the microbe safely, can have a relatively long production time, will likely require multiple doses to be administered, and may need to be given alongside an immune enhancer known as an adjuvant.

Covid-19 vaccine candidates currently in clinical trials that fall into this category include those developed by Wuhan Institute of Biological Products/Sinopharm, Beijing Institute of Biological Products/Sinopharm, Bharat Biotech, Chinese Academy of Medical Sciences, and Sinovac.

Another way to make a whole microbe vaccine is to use a living but weakened version of the microbe or again one that’s very similar. This is what is known as a live-attenuated vaccine. Again, this is well-established technology which has proved to be highly effective and the vaccines can be manufactured at a reasonable scale. The measles, mumps and rubella (MMR) vaccine and the chickenpox and shingles vaccine are good examples. The disadvantages are similar in that it still requires special laboratory facilities to grow the microbe safely, and can have a relatively long production time. More importantly though, vaccines like this may not be suitable for people with compromised immune systems.

Covid-19 vaccine candidates that fall into this category and are currently in clinical trials include those developed by Mehmet Ali Aydinlar University/Acıbadem Labmed Health Services, Codagenix/Serum Institute of India, and Indian Immunologicals Ltd/Griffith University.

A variation on the live-attenuated vaccine approach is to develop what is known as a chimeric vaccine. For this, we use the backbone of a less harmful or weakened microbe but engineer it to contain the protein(s) of the harmful microbe that the immune system recognises. Again, there are vaccines like this already in use in people, including for Ebola and dengue fever, and they have been shown to trigger really good immune responses. These vaccines also have the advantage that they don’t need the same level of specialist lab to grow the microbe and so are relatively quick to scale up.

This is the strategy of the University of Oxford/AstraZeneca vaccine which is a chimpanzee adenovirus backbone engineered to have the spike protein from the SARS-Cov-2 responsible for Covid-19. Adenoviruses are viruses that cause the common cold. The CanSino Biological Inc/Beijing Institute of Biotechnology Ad5 vaccine candidate uses a similar strategy, only instead of a chimpanzee adenovirus they have used a human adenovirus as the backbone. The disadvantage of using a human adenovirus is that people may have already been exposed to it in the past so they may have pre-existing antibodies which means they are less likely to mount a good immune response to the engineered version.

The protein/subunit approach

The next approach to making a vaccine is to just use the proteins (or sometimes sugars) from the virus or bacterium that the immune system needs to recognise. There are two strategies here. The first is to deliver the specific proteins – referred to as subunit vaccines. Most of the vaccines on the childhood schedule are this type, protecting us from diseases such as whooping cough, tetanus, diphtheria, and meningococcal meningitis.

Covid-19 vaccine candidates that fall into this category and are currently in clinical trials include those developed by Novavax, Anhui Zhifei Longcom Biopharmaceutical/Chinese Academy of Sciences, Clover Biopharmaceuticals Inc/GSK/Dynavax, Vaxine Pty Ltd/Medytox, and University of Queensland/CSL/Seqirus.

The second strategy is to use virus-like particles (VLPs) instead. These are self-assembled structures made from viral proteins that mimic the architecture of viruses. Importantly, they lack genetic material so aren’t able to replicate in host cells like an infectious virus would. Examples of this type of vaccine are the HPV and Hepatitis B vaccines. Medicago Inc are currently carrying out a phase 1 clinical trial of a plant derived VLP administered with an immune enhancing adjuvant.

The advantages of the protein subunit and VLP approach are that it’s well established technology that we know works in people, doesn’t involve growing any dangerous microbes, and the vaccines can be manufactured at a reasonable scale. The downsides are that they are expensive, and like the inactivated approaches the vaccines usually need to be given alongside an immune enhancing adjuvant which adds to the manufacturing process.

The genetic approach

The final approach to making a vaccine is to just use the genetic material that codes for the parts of the microbe that trigger our immune system. The idea is that by introducing the genetic material into our body, our cells will read the code and make the protein for our immune system to see. Again, there are two strategies here, the first is to use DNA, and the second to use RNA. If DNA is used, the cell makes RNA from that DNA and then protein from the RNA. Using RNA obviously skips the DNA to RNA step.

The advantages of this approach are that it is really quick to develop and really easy to upscale and manufacture. The main downside is that no vaccines developed using this technology have yet been approved for use in humans, though there have been human trials of DNA vaccines including those for cancer. The DNA approach also has the added downsides that delivery of the vaccine is quite difficult and there is the hypothetical risk that the DNA could integrate into the human genome whereas the RNA version cannot.

Inovio Pharmaceuticals/International Vaccine Institute, Osaka University/AnGes/Takara Bio, Cadila Healthcare Limited, and Genexine Consortium all have DNA vaccine candidates for Covid-19 in clinical trials. Moderna/NIAID, Imperial College London, Curevac, BioNTech/Fosun Pharma/Pfizer, and the People’s Liberation Army (PLA) Academy of Military Sciences/Walvax Biotech all have RNA candidates in clinical trials.

It’s incredible how quickly all of these vaccine candidates have been developed and how fast they are progressing into clinical trials. What’s crucial now is that those trials are well-designed and transparent so that we can be confident that that any vaccine that gets the green light is safe and  effective.