Inactivated COVID-19 vaccines effectively prevent death, but their effectiveness for preventing infection or severe illness is known to decrease within 3–6 months following the second priming dose. Here we aimed to evaluate the immunogenicity and safety of three potential booster vaccines administered as a full-dose homologous booster or full-dose or half-dose heterologous boosters among individuals primed with CoronaVac.
Between Nov 26 and Dec 16, 2021, 1015 people were screened, and 960 healthy adults were enrolled; 190–193 were included in each group. 28 days after receiving the booster, combining the 3 to less than 6 months and 6 to 9 months groups, the proportions of seroconversion rates in each vaccine group were ChAdOx1-S 75 (82%) of 92 to 87 (88%) of 99 for full dose and half dose, BNT162b2 92 (92%) of 100 to 90 (98%) of 92 for full dose and half dose, and CoronaVac in 38 (41%) of 92 to 65 (66%) of 98. All booster groups achieved 100% seropositivity 28 days after the booster dose. Participants in the 6 to 9 months priming group achieved higher titres compared with participants in the 3 to less than 6 months priming group. The geometric mean titres in participants in the 6 to 9 months priming group in each vaccine group were ChAdOx1-S 11258·69 (9562·43–13 255·85) and 7853·04 (6698·92–9206·00) for full dose and half dose, BNT162b2 19999·84 (17 720·58–22 572·25) and 17 017·62 (14 694·40–19 708·16) for full dose and half dose and CoronaVac 1440·55 (1172·81–1769·42) achieved higher titres compared with participants in the 3 to less than 6 months priming group which in each vaccine group were ChAdOx1-S 7730·39 (6401·87–9334·60) and 6684·34 (5678·94–7867·73) for full dose and half dose, BNT162b2 16594·08 (13 993·08–19 678·55) and 12 121·67 (9925·21–14 804·19) for full dose and half dose, and CoronaVac 1210·23 (976·49–1499·92). The median percentage inhibition for the surrogate virus neutralisation test against the delta B.1.617.2 and wild-type (WT) variant before the booster and 28 days after the booster dose was very high in all groups (p<0·001), all with greater than 90% inhibition against both delta and WT strains. No serious adverse events were associated with the vaccines. Within the heterologous booster groups, the adverse event rates in the half-dose groups were lower compared with the full-dose groups.
Geometric mean titre values between participants in the 6 to 9 months priming group and the 3 to less than 6 months priming group before the booster dose and between half-dose and full-dose groups 28 days before the booster were not significantly different for half-dose ChAdOx1-S, full-dose BNT162b2, and CoronaVac and were significantly different for full-dose ChAdOx1-S and half-dose BNT162b2. Among individuals primed with CoronaVac, boosting with BNT162b2 (full dose or half dose) or ChAdOx1-S (full dose or half dose) produces substantially better immune responses than in those boosted with CoronaVac. Full-dose and half-dose boosting with either BNT162b2 or ChAdOx1-S produced similar responses. Heterologous booster with half-dose might be considered in adults primed with two doses of CoronaVac vaccine.
Ministry of Health, Indonesia.
For the Indonesian translation of the abstract see Supplementary Materials section.
Results of a phase 3 clinical trial done in Indonesia indicated that CoronaVac reduces the incidence of COVID-19 by 65·3%.
The majority of COVID-19 vaccines used for priming in Indonesia are CoronaVac and ChAdOx1-S. However, the effectiveness of CoronaVac for preventing infection or severe illness diminishes, particularly in people aged at least 65 years.
Research in contextEvidence before this studyWe searched the peer-reviewed (PubMed) and preprint (MedRxiv) literature for studies published in English related to safety, reactogenicity, and tolerability of COVID-19 vaccines in healthy adults between Nov 1, 2021, and May 9, 2022, with no date restrictions, and using the search terms “COVID-19”, “vaccine”, combined with “safety”, or “reactogenicity”. We identified four original clinical studies on the immunogenicity and safety of full doses versus half doses of COVID-19 vaccine. A first study in Brazil established that antibody concentrations were low at 6 months after previous immunisation with two doses of CoronaVac. Heterologous boosting resulted in more robust immune responses than homologous boosting and might enhance protection. A second study established that a third dose of CoronaVac in adults administered 8 months after a second dose effectively recalled specific immune responses to SARS-CoV-2, which had declined substantially 6 months after two doses of CoronaVac, resulting in a remarkable increase in the concentration of antibodies and indicating that a two-dose schedule generates good immune memory, and a primary third dose given 2 months after the second dose induced slightly higher antibody titres than the primary two doses. A third study established that administration of either viral vector (AZD1222) or mRNA (BNT162b2) boosters in individuals with a history of two doses of inactivated vaccine (CoronaVac) obtained great immunogenicity with acceptable adverse events. A fourth study established that a booster dose of BNT162b2 given to individuals previously vaccinated with CoronaVac or ChAdOx1 is the most immunogenic and induced high cross-protective antibodies against delta, beta, and omicron variants, and T-cell response. We found no studies examining the immunogenicity and safety in healthy adults of full-dose versus half-doses of COVID-19 vaccine (ChAdOx1-S or BNT162b2) or full-dose CoronaVac administered as a booster dose after priming with CoronaVac in Indonesia.Added value of this studyOur study is the first observer-masked, randomised controlled trial to evaluate the immunogenicity and safety of the full dose or fractional dose of three potential COVID-19 booster vaccines among fully vaccinated individuals in Indonesia. We evaluate the immunogenicity and safety of three potential booster vaccines administered as a homologous booster and a full-dose or half-dose heterologous booster among fully vaccinated individuals. We show that participants who underwent CoronaVac priming within 3 to less than 6 months and 6 to 9 months before enrolment had low baseline pre-booster IgG anti-S-RBD titres. Our study shows that a booster dose administered 6 to 9 months after primary vaccination achieved a more robust immune response compared with a booster administered <6 months subsequent to two doses of primary vaccine. We also show that heterologous boosting with ChAdOx1-S and BNT162b2 induced a higher immune response compared with homologous boosting with CoronaVac.Implications of all the available evidenceHeterologous half-dose and full-dose vaccines as third doses resulted in more robust immune responses and were better tolerated than homologous full-dose vaccines and they might be considered after 6 to 9 months of two doses of primary vaccine.
The Government of Indonesia was planning for booster vaccinations by considering the low national vaccine supply. Several studies have shown that a fractional dose of a COVID-19 vaccine produces antibody and cellular immune responses similar to those achieved with the full dose.
Thus, if the fractional dose induces an adequate immune response, this will probably stretch the low global COVID-19 vaccine supplies. Findings from a global vaccine trial provide important insights into the potential merits of vaccinating people with fractional doses of COVID-19 vaccines.
Here we aimed to evaluate the immunogenicity and safety of three potential booster vaccines administered as a homologous booster and a full-dose or half-dose heterologous booster among fully vaccinated individuals.
Study design and participants
We did an observer and participant masked, randomised clinical trial to assess immune responses and safety after a booster dose with full-dose or half-dose ChAdOx1-S, full-dose or half-dose BNT162b2, or full-dose CoronaVac in clinically healthy adults aged at least 18 years who received two doses of the primary series of CoronaVac vaccine within 3 to less than 6 months or 6 to 9 months before enrolment in the study. The study also enrolled a cohort of participants who had previously received two priming doses of ChAdOx1-S. Here we report the results for participants administered CoronaVac priming. Recruitment of participants who had received ChAdOx1-S priming was in progress when this report was submitted for peer review. The results for the ChAdOx1-S participants will be reported when the study is completed.
The current study was done at five recruitment sites in Bandung and Jakarta, Indonesia as follows: Public Health Center (PHC) Garuda, PHC Ciumbuleuit, Health Clinic UNPAD, PHC Senen, and PHC Tambora. The study aimed to evaluate the antibody titres before and 28 days after the booster dose using heterologous or homologous vaccines and to evaluate the reactogenicity rates and severities within 24 h, 7 days, and 28 days for each booster vaccine group. Here we present the results from the CoronaVac priming population whose last visit for participants (28 days after the booster dose) occurred on Jan 14, 2022.
The Health Research Ethics Committee of the National Institute of Health Research and Development and the National Agency of Drug and Food Control of Indonesia approved this study. The protocol is included in appendix 2.
Randomisation and masking
Each participant was assigned a unique study identification number and randomisation code (A, B, C, D, or E) to receive intramuscularly either one booster dose of: BNT162b2 (0·3 mL), BNT162b2 (0·15 mL), ChAdOx1-S (0·5 mL), ChAdOx1-S (0·25 mL), or CoronaVac (0·5 mL).
Participants were randomly assigned and vaccinated by the unmasked personnel.
The COVID-19 vaccines were ChAdOx1-S, BNT162b2, and CoronaVac. Full-dose (standard dose) ChAdOx1-S vaccine refers to one dose (0·5 mL) containing chimpanzee adenovirus encoding the SARS-CoV-2 spike glycoprotein (ChAdOx1-S), greater than 2·5 × 108 infectious units. A fractional dose (0·25 mL) of ChAdOx1-S vaccine represents half the standard dose. Each standard dose (0·3 mL) of BNT162b2 contains 30 μg of a nucleoside-modified mRNA encoding the viral spike (S) glycoprotein of SARS-CoV-2. The fractional dose of BNT162b2 was 15 μg in 0·15 mL.
CoronaVac is a Vero cell-based, aluminium hydroxide-adjuvanted, β-propiolactone-inactivated vaccine based on the CZ02 strain. The standard dose of CoronaVac vaccine used in this study (0·5 mL) contains SARS-CoV-2 antigen (600 SU, 3 μg/0·5 mL). All vaccines were injected intramuscularly into the deltoid region.
After receiving a booster dose on day 0, participants were provided with a thermometer and diary cards to record post-vaccination adverse events. Reactogenicity data on the diary card were reviewed by the investigator after 30 min, 1 day (phone call), 7 days, and 28 days after the booster vaccination. The participant and the investigator who observed the reactogenicity were masked to the participant’s intervention group. Blood samples (10 mL) were collected on day 0 before the booster dose and 28 days post-booster dose. Blood samples were analysed for IgG antispike-receptor binding domain (anti-S-RBD) SARS-CoV-2 antibody by means of a chemiluminescent microparticle immunoassay from Abbott Laboratories at the Pathology Clinic Laboratory of Dr Hasan Sadikin Hospital in Bandung, Indonesia.
There were four major protocol deviations during the study (appendix 2 p 4).
Seroconversion in the surrogate virus neutralisation test (sVNT) was defined as the detection of antibody against SARS-CoV-2.
The secondary outcome was the incidence rate and intensity of adverse events within 24 h, 7 days, and 28 days after the booster dose.
To analyse immunogenicity, the comparison of geometric mean titre values between each booster group was calculated after logarithmic transformation. The IgG anti-S-RBD titre is presented as the geometric mean titre at a 95% CI. The Mann-Whitney test was used to compare the differences between the geometric mean titre values of full-dose and half-dose booster groups; and pina-registry.org, INA-GO0HLGB.
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, or data interpretation.
Among participants administered two doses of CoronaVac priming within 3 to less than 6 months before the ChAdOx1-S booster dose, geometric mean titre values 28 days after the booster were 7730·39 AU/mL (95% CI 6401·87–9334·60) for the full-dose group and 6684·34 AU/mL (5678·94–7867·73) for the half-dose groups (p=0·15). In participants administered two doses of CoronaVac priming within 6 to 9 months before the ChAdOx1-S booster dose, geometric mean titre value 28 days after the booster in the full-dose group was 11 258·69 AU/mL (9562·43–13 255·85) and for the half-dose ChAdOx1-S groups was 7853·04 AU/mL (6698·92–9206·00; p<0·05).
Among participants administered two doses of CoronaVac priming within 3 to less than 6 months before the BNT162b2 booster dose, geometric mean titre values 28 days after the booster were 16 594·08 AU/mL (95% CI 13 993·08–19 678·55) in the full-dose group and 12 121·67 AU/mL (9925·21–14 804·19) in the half-dose group (p=0·017). For participants administered two doses of CoronaVac priming within 6 to 9 months before the BNT162b2 booster dose, the geometric mean titre values 28 days after the booster dose were 19 999·84 AU/mL (17 720·58–22 572·25) for the full-dose group and 17 017·62 AU/mL (14 694·40–19 708·16) for the half-dose group (p=0·15).
Among participants administered two doses of CoronaVac priming within 6 to 9 months before the booster, the geometric mean titre values 28 days postbooster dose with full-dose ChAdOx1-S and half-dose BNT162b2 were significantly higher than in the 3 to less than 6 months group with the p value 0·009 and 0·013, respectively. This effect was seen in the other groups also but these were not significant with p value 0·176 for half-dose ChAdOx1-S, 0·154 for full-dose BNT162b2, 0·112 for CoronaVac.
The proportions of seroconversion rates in each vaccine group were ChAdOx1-S 75 (82%) for full dose to 87 (88%) for half dose, BNT162b2 92 (92%) for full dose to 90 (98%) for half dose, and CoronaVac in 38 (41%) for 3–6 months to 65 (66%) for 6–9 months.
The sVNT against delta and wild-type variant at 6 to 9 months after primary CoronaVac vaccination was lower than at 3 to less than 6 months in all groups. The median percentage inhibition for sVNT against the delta and wild-type variant at 28 days after the booster dose was over 90% for all groups (p<0·001 for all groups compared with day 0).
In their interim statement on Dec 16, 2021, WHO advised that vectored or mRNA vaccines are considered a third dose for those who received an inactivated vaccine as the initial dose.
Immune persistence analysis done in a study of immunogenicity and safety of a third dose of CoronaVac in China showed that regardless of the interval between the primary dose schedule (interval 14 or 28 days), neutralising antibody titres declined to below the seropositive cutoff by 6 months after the second dose.
Among participants who received two doses of CoronaVac priming within 6 to 9 months before the booster dose in the full-dose and half-dose ChAdOx1-S groups, the pre-booster geometric mean titre values were lower than in the 3 to less than 6 months groups, but at 28 days after the booster, responses were higher in the 6 to 9 months group (p<0·05).
The use of half doses as booster doses and a potentially primary series might spare many doses of vaccine, potentially freeing vaccines for communities without access to them.
Our study shows that all the booster doses administered 6 to 9 months after primary vaccination achieved a more robust immune response compared with a booster administered less than 6 months after primary vaccination. Boosting appears to bring titres up to a certain level, irrespective of their baseline starting point, and it is this starting point that is most affected by time since the priming series was completed. Waning vaccine efficacy, the local epidemic status, infection risk, and vaccine supply play important roles in establishing the optimal booster dose schedule.
In all the booster dose groups, the differences between the time since last primary dose were as expected: the 3 to less than 6 months groups had higher pre-existing antibody concentrations, whereas the 6 to 9 months groups had higher responses. These results might reflect a true underlying difference in both groups of unknown clinical significance. Further analysis examining the effect of pre-booster concentrations would be interesting.
showed that a third dose of CoronaVac (3 μg) administered 8 months after the second dose achieved increases in neutralising antibody titres that were 3 times to 5 times as high compared with titres 28 days after the second dose. In contrast, a third dose administered 2 months after the second dose induced comparatively much lower neutralising antibody titres. This observation might be explained by the short interval between the two doses during which memory B cells were immature. Another study found that although neutralising antibody titres decreased to near or below the lower limit of seropositivity 6 months after the second dose, a third dose administered 8 months after the second dose was highly effective in recalling a SARS-CoV-2-specific immune response, leading to a significant rebound in antibody concentrations.
The Thai study also found similar boosting with full-dose and half-dose ChAdOx1-S and BNT162b2 vaccines.
The homologous CoronaVac booster produced less reactogenicity than the heterologous booster vaccine, whereas the half-dose boosters of the ChAdOx1-S and BNT162b2 vaccines produced less reactogenicity than the full doses.
The intensities of most local and systemic adverse events encountered here were mild (grade 1) and started within 24 h after the booster. The most common local reaction was pain at the injection site, and the most common systemic reaction was headache. Participants administered the BNT162b2 booster, full dose or half dose, reported more adverse events compared with participants administered other booster vaccines. Participants who received a homologous booster of CoronaVac had the lowest adverse event rate.
The results of the present study complement the requirement of WHO for acquiring data illustrating the benefits of administering half doses of a heterologous booster. This approach potentially increases coverage and enhances immunisation booster services.
There are some limitations to our study. We used the sVNT assay to evaluate functional antibody rather than neutralising antibody titres against the live wild-type SARS-CoV-2 or omicron variant. In this report we have described immune responses after 28 days in the various vaccine groups. The results are reported following a short follow-up time. To truly assess the public health value of these booster regimens, we propose to follow the participants in this study for at least 12 months to monitor immunity and evidence of vaccine failures and report on functional antibody assays and cellular immunity assays in coming reports.
In conclusion, we show here that heterologous half-dose and full-dose ChAdOx1-S or BNT162b2 vaccines following CoronaVac priming were well tolerated and elicited a strong immune response. Half-dose heterologous boosting might therefore serve as a useful approach following initial vaccination with an inactivated COVID-19 vaccine.
BCOV121 study group
Eddy Fadlyana, Djatnika Setiabudi, Cissy B Kartasasmita, Nina Dwi Putri, Sri Rezeki Hadinegoro, Kim Mulholland, Yulia Sofiatin, Hendarsyah Suryadinata, Yovita Hartantri, Hadyana Sukandar, Agnes R Indrati, Chrysanti Murad, Vivi Setiawaty, Krisna Nur A Pangesti, Pretty Multihartina, Citra Vravita Khrisna, Masayu Riela Ayuninda, Pratama Wicaksana, Aqila Sakina Zhafira, Robert Sinto, Kusnandi Rusmil, Julitasari Sundoro, Emma Watts, Cattram Nguyen.
EF, CBK, KM, EW, ARI, CM, NDP, DS, KNAP, VS, HS, and CVK had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. EF, CBK, KM, SRH, KR, and EW conceptualised the study. EF, DS, NDP, HS, YH, YS, MRA, PW, ASZ, RS, and CVK did the study, recruited the participants, and collected data. ARI, CM, VS, and KNAP managed sample collection and the laboratory analyses. PM monitored the trial. HS contributed to statistical analysis of the data. EF and CVK wrote the original draft of the manuscript. KM, DS, NDP, HS, ARI, CM, VS, KNAP, YS, YH, PW, ASZ, RS, EW, CBK, SRH, JS, and KR reviewed the manuscript. CBK, SRH, JS, and KR were the medical advisers and provided supervision. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Declaration of interests
PM is employed by the National Institute of Health Research and Development. CBK, SRH, and JS are members of the Indonesian Technical Advisory Group on Immunization. All other authors declare no competing interests.
The National Institute of Health Research and Development, Ministry of Health, Republic of Indonesia funded and supplied the vaccines used in this study. The authors thank the participants for their valuable contributions, and all those who contributed to support this study. All authors approved the manuscript and agreed with the decision to submit the manuscript for publication.
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