China’s CoronaVac and Sinopharm vaccines account for almost half of the 7.3 billion COVID-19 vaccine doses delivered globally, and have been enormously important in fighting the pandemic, particularly in less wealthy nations.
But as the doses mount, so have the data, with studies suggesting that the immunity from two doses of either vaccine wanes rapidly, and the protection offered to older people is limited. This week the World Health Organization announced advice from its Strategic Advisory Group of Experts on Immunization (SAGE) that people over 60 should receive a third dose of the same or another vaccine to ensure sufficient protection.
The recommendation is “sensible and necessary”, says Manoel Barral-Netto, an immunologist at the Oswaldo Cruz Foundation in Salvador, Brazil.
A number of countries are already offering third doses to all adults or are trying mix-and-match approaches. Some experts are even questioning whether China’s jabs — based on inactivated virus — should continue to be used at all when other options are available.
But others say that the vaccines still have a major part to play. “These are not bad vaccines. They’re just vaccines that haven’t been optimized yet,” says Gagandeep Kang, a virologist at the Christian Medical College in Vellore, India, who advises SAGE.
CoronaVac, produced by Beijing-based company Sinovac, is the world’s most widely used COVID-19 vaccine. Not far behind is the vaccine developed in Beijing by state-owned Sinopharm (see 'The race to vaccinate').
In mid-2021, the World Health Organization (WHO) approved the shots for emergency use, on the basis of limited clinical-trial data suggesting that CoronaVac was 51% and Sinopharm 79% effective at preventing symptomatic disease. This was on a par with the 63% efficacy reported for the University of Oxford–AstraZeneca’s viral-vector vaccine at the time of its WHO listing, but lower than the 90% and higher efficacies of the mRNA vaccines developed by Pfizer–BioNTech and Moderna.
Both the Chinese vaccines are inactivated vaccines, which use killed SARS-CoV-2 virus. Researchers say this type of vaccine seems to be less potent because it triggers an immune response against many viral proteins. By contrast, mRNA and viral-vector vaccines target the response to the spike protein, which is what the virus uses to enter human cells.
“You don’t choose the target with inactivated vaccines, you just throw in all these different antigens,” explains Jorge Kalil, a physician and immunologist at the University of São Paulo Medical School, Brazil.
About 2.4 billion doses of the Chinese vaccines have been administered in China, but almost 1 billion doses have gone to 110 other countries (see 'Biggest takers for China's vaccines'). Reports earlier this year of COVID-19 surges in several countries that had vaccinated many people with these vaccines — such as the Seychelles and Indonesia — prompted questions about the protection they offered.
Numerous studies have now been undertaken in nations including Brazil, Chile and Thailand, to understand waning immunity and protection in different groups.
Lower antibody responses
Some studies have found that compared with vaccines made using other technologies, China’s inactivated vaccines initially generate lower levels of ‘neutralizing’ or virus-blocking antibodies — considered a proxy for protection — and that these levels drop quickly over time.
One study of 185 health-care workers in Thailand1, not yet peer-reviewed, found that 60% had high levels of neutralizing antibodies one month after receiving a second dose of CoronaVac, compared with 86% of those who had received two shots of the Oxford–AstraZeneca vaccine.
Co-author Opass Putcharoen, an infectious-diseases specialist at the Thai Red Cross Emerging Infectious Diseases Clinical Center in Bangkok, says the team also found that three months after receiving the second CoronaVac shot, the antibody prevalence dropped to just 12%.
But “waning of antibodies isn’t necessarily the same as waning of immune protection”, says Ben Cowling, an epidemiologist at the University of Hong Kong. He says that vaccines induce complex immune responses, including B cells and T cells, which might be more long lived than neutralizing antibodies.
One study from Hong Kong2, which has not been peer-reviewed, showed that CoronaVac induces a significantly lower antibody response compared with Pfizer–BioNTech’s mRNA jab one month after two doses, but that the T-cell response was comparable.
Another non-peer-reviewed study, of health-care workers in China3, also found that B cells and T cells specific for SARS-CoV-2 could be detected five months after two doses of the Sinopharm vaccine.
So far, studies assessing protection over time are limited. But preliminary analysis of a mass-vaccination campaign with CoronaVac in Chile suggests a small but significant decline in efficacy against symptomatic disease, although protection against hospitalization remains high, says Eduardo Undurraga, a public-health researcher at the Pontifical Catholic University of Chile in Santiago.
Vaccines made using other technologies have seen a similar trend of waning antibodies and protection against infection, but more-robust protection against severe disease and death. But researchers say that because the Chinese inactivated vaccines start at a lower base of neutralizing antibodies, the protection they offer could drop faster than those with a stronger head start.
To boost, or not to boost
The less-potent immune response from inactivated vaccines also has implications for the protection they offer to older people. The immune system weakens with age and vaccines are generally less effective in older people, says Kang, but the effect seems to be more pronounced with the inactivated vaccines.
A massive analysis of some one million people who were hospitalized with COVID-19 in Brazil4 found that CoronaVac offered up to 60% protection against severe disease up to the age of 79 — not far off the 76% protection offered by the Oxford–AstraZeneca vaccine.
But the picture changes drastically in people over 80, says co-author Daniel Villela, an epidemiologist at the Oswaldo Cruz Foundation at Rio de Janeiro, Brazil. In that group, CoronaVac was only 30% effective at preventing severe disease and 45% effective against death, compared with 67% and 85%, respectively, for the Oxford–AstraZeneca jab.
Research by Barral-Netto and his colleagues5 found that CoronaVac prevented only 33% of deaths due to COVID-19 in people 90 and older. Neither study has been peer-reviewed, but Villela says they influenced Brazil’s government to start giving people older than 70 a third shot of an mRNA or viral-vector vaccine in August — that decision has now been extended to people older than 60.
“It was better to receive CoronaVac than nothing,” says Barral-Netto, but now that other vaccines are flowing into Brazil “it is probably not very wise to keep vaccinating people with this vaccine”, he says, adding that the Brazilian government has said it will stop purchasing CoronaVac.
Other countries, including Chile, Abu Dhabi in the United Arab Emirates and China, are also giving booster jabs to those who received the CoronaVac or Sinopharm vaccines.
Clinical-trial data from China6, not yet peer-reviewed, suggest that a third dose of CoronaVac increases neutralizing antibody levels, and a similar boost has been observed in studies of third doses of Sinopharm’s vaccine.
And earlier this month, the Chilean government reported preliminary results on the effectiveness of booster shots, based on data from some two million people who had received two shots of CoronaVac, and a third shot of the CoronaVac, Pfizer–BioNTech or Oxford–AstraZeneca vaccines. Protection against COVID-19 jumped from 56% after two shots to 80% or higher after a third shot of any vaccine, with protection against hospitalization rising from 84% to 87%.
Mix and match
Some researchers say an alternative to a three-dose schedule might be to mix and match with just two doses.
Sompong Vongpunsawad, a virologist at Chulalongkorn University in Bangkok, led a team that looked at antibody levels in 54 people who received one dose of CoronaVac and one of Oxford–AstraZeneca. The results7, not yet peer-reviewed, suggested that the immune response was similar to two doses of AstraZeneca, and higher than two doses of CoronaVac.
Vongpunsawad says the finding is useful in places where doses of some vaccines are in short supply. “It was like bingo — we can actually solve the vaccine limitation crisis,” he says. The result spurred the Thai government to recommend mix-and-match schedules, he says.
A trial in China also found that using an adenovirus-vector vaccine produced by the Tianjin-based company CanSino Biologics, in addition to one or two doses of CoronaVac, induced higher neutralizing antibody levels, compared with two doses of CoronaVac alone8.
It is not yet clear how long that protection will last, and how these antibody levels translate to actual protection, but researchers say such mixing has merit.
“For all vaccines, it’s very much an evolving situation,” says Kang. “Inactivated vaccines are a big part of our portfolio. So we really need to figure out how to use them.”
Nature 598, 398-399 (2021)
Jantarabenjakul, W. et al. Preprint at medRxiv https://doi.org/10.1101/2021.08.27.21262721 (2021).
Ka Pun Mok, C. et al. Preprint at SSRN https://doi.org/10.2139/ssrn.3884943 (2021).
Liu, Y. et al. Preprint at medRxiv https://doi.org/10.1101/2021.09.12.21263373 (2021).
Villela, D. A. M. et al. Preprint at medRxiv https://doi.org/10.1101/2021.09.10.21263084 (2021).
Cerquiera-Silva, T. et al. Preprint at medRxiv https://doi.org/10.1101/2021.08.21.21261501 (2021).
Li, M. et al. Preprint at medRxiv https://doi.org/10.1101/2021.08.03.21261544 (2021).
Yorsaeng, R. et al. Preprint at medRxiv https://doi.org/10.1101/2021.09.01.21262955 (2021).
Li, J. et al. Preprint at medRxiv https://doi.org/10.1101/2021.09.03.21263062 (2021).