Creating a universal vaccine is itself highly challenging. For example, scientists have tried for years but not yet succeeded in developing a universal vaccine for flu. Nor have they yet managed to create one for HIV. In part, this is because the surface proteins found on these viruses frequently change their appearance. This makes it difficult for our immune system to recognise the virus.
But scientists have made enormous advances in recent years in understanding the interaction between the immune system and viruses that cause flu and HIV. They are now deploying this knowledge to build a universal vaccine for coronaviruses, which do not change as fast.
A long history of vaccine innovation
One of the reasons for optimism with a universal coronavirus vaccine is the successful development of the SARS-CoV-2 vaccine. Made in record time, the foundation for the vaccine was laid many years ago. Until the 1980s most vaccines were developed by modifying a virus or bacteria to make it no longer dangerous. This was achieved by weakening or inactivating the pathogen so that it could be injected safely to stimulate an immune response. While highly successful for protecting against a host diseases like measles, polio, rabies and chickenpox, this approach didn’t prove effective in all diseases.
By the 1980s vaccine production stood on the cusp of change helped by the emergence of biotechnology. Where this was first successfully applied was in the development of a vaccine against hepatitis B, which is estimated to cause more deaths worldwide than TB, HIV or malaria.
The first hepatitis B vaccine was developed by Maurice Hilleman at Merck. Approved in 1981, it was the first vaccine to protect against cancer. Chronic hepatitis B is a major cause of liver cancer. In fact, it is second only to tobacco as a human carcinogen. What was novel about the hepatitis B vaccine was that instead of using the whole hepatitis B virus, which was difficult to grow in the laboratory, it used only a coat surface particle of the virus. This was a major breakthrough for vaccine technology.
Another vaccine that uses virus particles is the one against the human papillomavirus (HPV) which causes cervical cancer, a disease that globally kills 260,000 women every year. First licensed in 2005, the HPV vaccine took years to develop. It consists of tiny proteins that look like the outside of four types of real HPV produced in yeast.
Vaccine technology underwent a further revolution following the outbreak of the swine flu pandemic that swept the world for 19 months from January 2009. The pandemic killed between 151,700 and 575,400 people worldwide. Caused by an H1N1 influenza virus, the episode was an important reminder of the speed that pandemics can strike and the chaos they can sow. It was also a salutary lesson for companies who developed hundreds of millions of licensed vaccine doses to counter the pandemic. Although achieved within just six months, a historical record, this was not fast enough – by then the peak of infections had passed.
Part of the delay was because of the time it took to grow enough of the virus in eggs or cultured mammalian cells. Another method, using genetic engineering to produce the virus, proved much faster, but was hampered by regulatory hurdles. Determined to accelerate vaccine availability for future pandemics, from 2011, vaccine experts put in place a new strategy that took advantage of advances in genomics and the open sharing of electronic sequence data. Coupled with a new ability to synthesise genes, these tools gave scientists the power to design genome segments from a virus to prepare vaccines to train the body to recognise and target a real virus if it invaded.
Critically, the new synthetic approach moved vaccine development away from the time-consuming process of isolating and shipping viruses between different sites and then growing them at scale. All that was needed was to download the relevant sequence data from the internet and synthesise the right genes to generate relevant viral components to start vaccine development. Speed was not the only advantage the new method offered. It also reduced any potential biohazard risksinvolved in manufacturing the vaccine.
Attention was also paid to making the testing process more efficient. Usually the slowest part of vaccine development, such testing often takes years to complete. Tests are first conducted in animals, to assess the safety, the strength of the immune response stimulated and protective efficacy of the vaccine candidate. Once this is done it is tested in humans.
Human trials are run in three phases, each with increasing numbers of people and escalating costs. One means to reduce the time needed and cut costs was to take advantage of new biomarkers. These provided a means to measure both normal and pathological processes as well as responses to a drug. Such biomarkers made it possible to determine the toxicity and efficacy of a candidate much earlier in the clinical trial process and to run multiple trials in parallel without compromising on safety.
In 2011, a group of scientists from the companies Novartis and Synthetic Genomics, as well as the Craig Venter Institute (a non-profit research organisation) proved they could develop a vaccine candidate in a matter of days.
Their approach was first successfully put to the test in March 2013 when Chinese health officials reported a novel strain of avian influenza had infected three people. Within just a week of gaining access to the virus’s genome sequence, the Novartis team, headed by Rino Rappoli, managed to create a fully synthetic RNA-based vaccine ready for pre-clinical testing, which proved safe and elicited a good immune response.
Marking the switch from what Rappouli calls “analogue vaccines” to “digital vaccines”, the 2013 work provided a template for when COVID-19 was declared a pandemic on March 11, 2020. The first dose of the COVID-19 vaccine candidate, developed by Moderna, was ready for phase I testing in humans by March 16 2020. Many other vaccine candidates soon entered the pipeline thereafter.
What also helped propel the first COVID-19 vaccines forward was the explosion in knowledge about the atomic structure of proteins found on the surface of viruses and antibodies that bound to them. According to Ward this was greatly helped by advances in cryo-electron microscopy which as he says “opened up the door for HIV and other pathogens”. With the technique, Ward and his colleagues discovered that coronaviruses gained entry and fused with human cells with the help of a small loop of amino acids, called S-2P, on the top of their spike proteins. This laid an important foundation for creating the COVID-19 vaccines.
Another critical development was the discovery of broadly neutralising antibodies (bNAbs). First isolated in the early 1990s in the serum of people living with HIV-1, these antibodies only appear in some people after years of infection. Such antibodies have the advantage that they can neutralise multiple diverse strains of the virus in one stroke.
Finding the bNAbs critically opened up a new avenue for vaccine design. In particular, it offered the possibility of creating a universal vaccine against flu and also a vaccine for HIV which so far has been difficult to do because it mutates so fast. Several groups had already made progress in this field before COVID-19 struck, which they quickly turned towards coronaviruses. Their goal was to create a vaccine to stimulate the production of bNAbs targeting the receptor binding domain (RBD) located on the coronavirus’ spike protein.