Immunogenicity to BNT162b2 booster in adults who had previously received inactivated COVID-19 vaccination

The ongoing coronavirus disease 2019 (COVID-19) pandemic has severely disrupted the world in terms of the disease burden and the economic impact of the restrictions imposed on ordinary social interactions outside the household. The only effective way out of the situation is by achieving population immunity, by natural infection, or via vaccination.

Study: BNT162b2 vaccine boosts neutralizing antibodies to ancestral SARS-CoV-2 & Omicron variant in adults received 2-dose inactivated vaccine. Image Credit: Tamer Adel Soliman/Shutterstock

However, the immunity achieved by vaccination has shown itself to be not foolproof, and the neutralizing antibodies elicited by the vaccine spike antigen not only wane rapidly, by about 6-9 months but are escaped by some variants of the virus-like the Beta and the Omicron. This has given rise to the recommendation to enhance immunity by a third booster dose.

A new preprint available on medRxiv* demonstrates the marked improvement in the immune response when the messenger ribonucleic acid (mRNA) vaccine BNT162b2, from Pfizer/BioNTech, is used for the third dose after a primary two-dose series of an inactivated whole virus vaccine.


Earlier studies showed that primary-series vaccination with the CoronaVac (Sinovac) inactivated virus vaccine produced lower levels of antibodies to the virus after compared to two doses of BNT162b2. The former showed a rapid decline in antibody titer and immune escape by the Delta and Omicron variants. This led to a third dose of the vaccine being offered, with trials still on to determine the best dose, interval, and age group.

In one such study, the titer of neutralizing antibodies went down to undetectable levels at 5-8 months from the second dose of CoronaVac. Still, it was restored by a third homologous vaccine dose, without an increased incidence of adverse events. Heterologous third dose boosters using BNT162b2 after primary-series CoronaVac vaccination have also been shown to boost the neutralizing titer by 1.4-fold against Omicron, compared to two doses of an mRNA vaccine.

Notably, the neutralizing titer was >6-fold and ~3-fold lower against Omicron compared to the wild-type or Delta variant, respectively. The current study is the first to assess the immune response to an mRNA vaccine used as a third dose booster after two doses of an inactivated vaccine. This is a real-world possibility since many developing countries have rolled out inactivated vaccines on a large scale due to their increased stability and the fact that they do not need ultra-cold storage conditions.

What did the study show?

The study was carried out on >300 participants, mostly Chinese adults with a median age of 47 years. Over a third were obese, and one in three had one or more comorbid conditions, such as high cholesterol, blood sugar, or blood pressure.

Almost all had received two doses of CoronaVac, and the rest another inactivated vaccine. About three-quarters had received the second dose 6-7 months before the study. Antibody study was carried out on Day 28. The study continued, with follow-up sampling planned for Day 182 and Day 365, respectively.

The antibody levels were significantly enhanced by the third dose of BNT162b2, with sVNT inhibition increasing from 17% to 96%. The neutralizing titer against the ancestral virus went up more than 27-fold over 28 days, with 90% of samples showing positive results even at the highest dilution of 1:320. This was also the case with the estimation of neutralizing titers sufficient to neutralize 90% of the viral particles from cell infection, with 12/20 samples being positive at 1:320 – a rise of 46-fold at least, over the 28-day study period.

Against Omicron, the 50% and 90% neutralizing activity rose 14-fold and 5-fold, respectively, by day 28. Thus, there was only a weak response against Omicron compared to the ancestral virus.

Within seven days of the third dose, most participants reported some symptoms, but these failed to subside in only 3 participants after this period. The most common symptoms in almost half the participants were pain and injection site swelling or hardness in a quarter. Others included headache, fever, muscle pain, fatigue and drowsiness, and a general feeling of being unwell.

Flu-like symptoms, gastrointestinal symptoms, and systemic features like skin rash or joint pain occurred in less than a tenth. Four sought medical advice within 7 days of the third dose, but there were no hospitalizations.

What are the implications?

Two doses of an inactivated COVID-19 vaccine led to a moderate rise in antibody titers at one month from the second dose, followed by a gradual decrease. A third dose boosted this. While a third dose of the same vaccine led to a 21-fold rise in neutralizing titers against the wild-type strain, as shown by earlier studies, the current study showed a 27-fold rise in titer when the third dose was of the mRNA vaccine BNT162b2.

Although the inactivated virus vaccine was directed against the wild-type vaccine, the heterologous booster increased 50% neutralizing titers against Omicron at least 14-fold. This is higher than the neutralizing titers against the wild-type virus after two CoronaVac doses. These levels were estimated to reduce the risk of infection with the wild-type virus by half at least. In that case, it would be expected to provide the same level of protection against Omicron.

In this high-risk population, the increase in neutralizing titer with the third dose of vaccine using the mRNA vaccine at about 6 months after two doses of inactivated vaccine is likely to be a significant contribution to protective immunity against wild-type as well as Omicron variants, especially as no neutralizing antibody to the latter is detectable at 3-4 months from the second dose.

While better vaccines that elicit broadly neutralizing immunity against multiple SARS-CoV-2 variants, or even against coronaviruses in general, are being sought, the researchers conclude,

Administering a third dose mRNA vaccine about 6-7 months after two doses of inactivated vaccines should be considered as an alternative to homologous third dose with an inactivated vaccine before vaccines updated with emerging variants are available.”

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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