Two COVID-19 Vaccine Candidates Induce Immune Response In Healthy Volunteers
Scientist conducting coronavirus vaccine research at NIAID’s Vaccine Research Centre, Moderna’s original collaborator on the SARS-CoV-2 vaccine.

A COVID-19 vaccine candidate made by Chinese researchers successfully induced the development of neutralizing and binding antibodies against SARS-CoV-2, the virus that causes COVID-19, according to early results from a non-randomized phase I clinical trial published Friday in The Lancet

The trial results follow on to results announced by Moderna earlier this week, which found that their vaccine candidate was able to induce neutralizing antibodies in 8 healthy volunteers. In vaccine trials, the development of neutralizing antibodies is the most sought-after immune response because these antibodies bind to viral particles in a way that immediately blocks infection.

The non-randomized Chinese study, which was published in The Lancet, reported preliminary safety and efficacy results for a vaccine in 108 healthy middle-aged adults at low, medium, and high doses; with 36 participants enrolled in each dosage level. At low dose and middle-doses, about a half of the individuals produced neutralizing antibodies after 28 days. At high doses, some three-quarters (27/36) of volunteers produced neutralizing antibodies. Regardless of vaccine dosage, over 90% of participants showed a four-fold increase in binding antibodies. 

“These results represent an important milestone,” said Wei Chen from the Beijing Institute of Biotechnology, who was responsible for the study. “The trial demonstrates that a single dose of the new adenovirus type 5 vectored vaccine produces virus-specific antibodies and T cells in 14 days, making it a potential candidate for further investigation.”

The Ad5-nCoV vaccine also stimulated a rapid T cell response in 83.3% of individuals that received a low dose – and in the medium and high- dose groups,  97% (35/36) of individuals exhibited rapid T cell responses. Certain types of T cells develop responses when exposed to specific antigens, or parts of disease-causing pathogens, and “remember” to attack the same pathogen once exposed to it again. Vaccines, which contain un-infective pieces of viruses or weakened viruses, help activate this immune memory by inducting a T-cell mediated response.

The most common adverse reactions to the vaccine persisted for less than 48 hours, which is usually considered acceptable for a vaccine. Side effects ranged from mild pain at the injection site reported in over half (54%, 58/108) of vaccine recipients, as well as fever (46%, 50/108), fatigue (44%, 47/108), headache (39%, 42/108), and muscle pain (17%, 18/108). 

Many Limitations to Chinese Vaccine Study & Concerns with the Adenovirus 5 Vector

Still, “the challenges in the development of a COVD-19 vaccine are unprecedented, and the ability to trigger these immune responses does not necessarily indicate that the vaccine will protect humans from COVID-19,” warned Chen.

Further, randomized trials are needed to tell whether the immune response the vaccine candidate elicits effectively protects against SARS-CoV-2 infection, he added.

And health experts have brought up concerns around the vector used to carry the vaccine, a weakened common cold-causing virus, adenovirus type 5 or Ad5.

“There has been a shadow with the Ad5 as a vaccine vector over the last decade, not seen with other Ad vectors for vaccines. Have these concerns been allayed?” tweeted Jeremy Farrar, director of the research foundation Wellcome Trust, in response to the study.

Farrar referred to a previous case where an HIV-vaccine candidate using the Ad5 vector was found to put study participants who received the vaccine at a higher risk of HIV infection – and further exploration of that vaccine candidate was promptly discontinued. It’s been posited that the T-cells activated by the Ad5-vector HIV vaccine candidate made the cells more vulnerable to infection by HIV-1, which attacks immune cells.

Of the concerns, the study authors write, “although the association between HIV-1 acquisition risk and Ad5 vectored vaccine is controversial and its mechanism is unclear, the potential risks should be taken into account in studies with this viral vector delivery platform.

“We plan to monitor the participants in our upcoming phase 2 and phase 3 studies to assess the indication for any such acquisition.” At least two other vaccine candidates using the Ad5 vector are listed in the World Health Organization’s draft registry of SARS-CoV-2 vaccine candidates, the study authors say.

However, another concern is that half of the participants in the COVID-19 vaccine trial also already had immunity to the Ad5 virus, and these participants showed weaker immune responses to the COVID-19 vaccine. 

“Our study found that pre-existing Ad5 immunity could slow down the rapid immune responses to SARS-CoV-2 and also lower the peaking level of the responses,” said Feng-Cai Zhu from Jiangsu Provincial Center for Disease Control and Prevention in China, part of the group that led the study. “Moreover, high pre-existing Ad5 immunity may also have a negative impact on the persistence of the vaccine-elicited immune responses.”

The authors note that the other limitations of the trial are its small sample size, relatively short duration, and most importantly, lack of a randomised control group – which may have biased their results.

To address these limitations, a randomised, double-blinded, placebo-controlled phase 2 trial in 500 healthy adults has been initiated in Wuhan to determine whether the results can be replicated, and if there are any adverse events up to 6 months after vaccination. For the first time, this will include participants over 60 years old, an important target population for the vaccine.

Moderna Vaccine Induces Immune Response In Limited Number Of Healthy Volunteers

In a parallel development, eight people injected with Moderna’s experimental COVID-19 vaccine, mRNA-1273, developed neutralizing antibodies against the virus, announced the US-based pharmaceutical firm on Monday.

Neutralizing antibodies were detected in 4 participants that were given a low vaccine dose of 25 micrograms, and in 4 others that received a higher dose of 100 micrograms, 43 days after receiving the vaccine. At these doses, the vaccine was generally safe and well tolerated, said Moderna in a statement.

Neutralizing antibody titers for the remaining study participants were not yet available. The data were from a Phase I clinical trial conducted in collaboration with the US National Institute for Allergies and Infectious Diseases (NIAID). 

“These interim Phase 1 data, while early, demonstrate that vaccination with mRNA-1273 elicits an immune response of the magnitude caused by natural infection starting with a dose as low as 25 micrograms,” said Tal Zaks, M.D., Ph.D., Chief Medical Officer at Moderna.

“When combined with the success in preventing viral replication in the lungs of a pre-clinical challenge model at a dose that elicited similar levels of neutralizing antibodies, these data substantiate our belief that mRNA-1273 has the potential to prevent COVID-19 disease and advance our ability to select a dose for pivotal trials,” added Zaks.

Based on these early results, Phase 2 trials for the Moderna vaccine were amended to include a 50 ug dosage and a 100ug dosage in order to finalize a dosage for Phase 3 studies. A 50ug dosage arm was added to the Phase 1  – NIAID study.

Phase 3 clinical trials could be initiated as soon as July 2020, an unprecedented speedy timeline for vaccine development.

However, similar to the Chinese vaccine study, the initial results don’t necessarily show that the vaccine induces an immune response strong enough to protect against COVID-19, nor do they show how long protection might last.

The concentration of neutralizing antibodies in the 8 participants was similar to the concentration found to be protective against COVID-19 in mouse models, although the results from animal models do not necessarily always correlate directly with humans. The 8 participants with neutralizing antibodies were sampled only two weeks after receiving the second dose of vaccine, and must be followed further in order to determine whether and for how long the neutralizing antibodies could protect against SARS-CoV-2 infection. 

Some 45 participants also developed ‘binding antibodies’, which can bind to a virus but do not make it less infectious.

Though Moderna’s vaccine study was led by the US National Institute of Allergy and Infectious Diseases (NIAID), the NIAID did not publish a press release, and declined to comment on Moderna’s announcement. If successful, this would be the first vaccine candidate that Moderna, a company that is experimenting with new, mRNA vectors for carrying vaccines, will bring to market. 

In recent months, health experts and government leaders are more and more pinning their hopes to quash the pandemic for good on a successful COVID-19 vaccine, as serological studies are beginning to show that a large proportion of countries’ populations will remain susceptible to the virus after the first wave.

Not everyone that gets infected with COVID-19 develops antibodies, suggest recent European serological surveys. In Switzerland, one of the hardest-hit countries in Europe, only 1 in every 10 people had antibodies against COVID-19 – and older people had about half as many antibodies as young and middle-aged individuals. 

Surveys in Spain and France also paint a solemn picture of immunity, as only about 4-5% of the population has detectable antibody levels. Though the number of people with antibodies is growing rapidly as infections increase, herd immunity is far away.

The creation of an effective vaccine is seen as the long-term solution to controlling the COVID-19 pandemic. Currently, there are more than 100 candidate COVID-19 vaccines in development worldwide.

Image Credits: NIAID.