Contribution of low population immunity to the severe Omicron BA.2 outbreak in Hong Kong

doi:10.21203/rs.3.rs-1512533/v1

Download PDF

Article

Contribution of low population immunity to the severe Omicron BA.2 outbreak in Hong Kong

https://doi.org/10.21203/rs.3.rs-1512533/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 24 Jun, 2022

Read the published version in Nature Communications →

Version 1

posted

You are reading this latest preprint version

Monitoring population protective immunity against SARS-CoV-2 variants is critical for risk assessment. In this serosurveillance study, older adults show much lower seropositive rates of neutralizing antibody (NAb) against ancestral virus than the younger population. The increase in NAb seopositive rate generally follows the population vaccination uptake rate, but older adults have a much lower NAb seropositive rate than vaccination uptake rate. For all age groups, the seropositive rates of NAb against Omicron variant are much lower than those against the ancestral virus. During the fifth wave of COVID-19 in Hong Kong which is dominated by Omicron sublineage BA.2, the case-fatality rate is exceptionally high in the ≥80 year-old age group (9.2%). Our study suggests that the severe BA.2 outbreak in Hong Kong can be attributed by the lack of protective immunity in the population, especially among the vulnerable older adults, and highlights the importance of continual surveillance of protective immunity against emerging variants of SARS-CoV-2.

COVID-19

SARS-CoV-2

Omicron variant

BA.1 and BA.2 sublineages

surveillance

neutralizing antibody

surrogate neutralization test

outbreak

older adults

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is characterized by efficient person-to-person transmission, propensity to cause severe disease, and frequent emergence of variants that escape population immunity ^{1, 2, 3}. The rapid surge of severe cases which require hospitalization, especially apparent during the emergence of novel variants, routinely overwhelms the healthcare systems. Governments have imposed stringent non-pharmaceutical public health interventions to curb the spread of COVID-19. While effective in limiting the spread of the virus, these measures have resulted in undesirable mental health and socioeconomic consequences. It has been estimated that COVID-19 was associated with an additional 53.2 and 76.2 million cases of depressive and anxiety disorders, respectively ⁴. School closure has led to psychosocial issues in children ⁵. Moreover, there is a significant economic impact due to COVID-19 ⁶. Lockdowns are also associated with disruptions in supply chains ⁷.

Forecasting the severity of upcoming COVID-19 waves is a critical component in formulating public health preparedness plans. Knowledge of the population level immunity against SARS-CoV-2 can help to predict the impact of COVID-19 on the healthcare system. COVID-19 vaccination or SARS-CoV-2 infection induce protective immunity against SARS-CoV-2 ⁸. A population with high vaccination uptake rate or incidence of infection theoretically have a high level of population immunity. However, several factors can affect the humoral immunity elicited by vaccination or infection ⁹. First, some COVID-19 patients or vaccine recipients do not develop sufficient protective antibody responses. Lower neutralizing antibody (NAb) titers are found in patients with asymptomatic or mild COVID-19, immunocompromised patients and older adults ^{10, 11, 12, 13, 14, 15, 16}. Second, the NAb titers elicited by inactivated whole virion or adenovirus-vectored vaccines are lower than those elicited by mRNA vaccines ^{17, 18, 19}. Third, NAb titers decline within a few months after infection or vaccination ^{20, 21, 22, 23, 24, 25, 26}. Fourth, NAb elicited from prior infection or vaccination may not be effective against new variants with mutations in the spike proteins, as in the case of Omicron variant ^{17, 26}.

In view of the shortcomings of using history of vaccination or infection to predict population immunity, a more reliable method to determine population level immunity would be to assess known correlates of protection. NAb titers showed a good correlation with vaccine effectiveness against symptomatic infection ^{18, 27}. In a clinical trial of the mRNA-1273 vaccine, the estimated vaccine efficacy decreased from 96% for a NAb titer of 1000 IU/ml to 78% for a NAb titer of 10 IU/ml ²⁸. Furthermore, individuals positive for anti-spike antibody, which correlates with NAb status, are less likely to have COVID-19 reinfection to cognate variants ²⁹.

With zero-case strategy, Hong Kong had a very low incidence of COVID-19, with a cumulative count of just 12,655 cases (0.17% of the population) as of December 2021. Local transmission of SARS-CoV-2 was almost absent from May to December 2021. The COVID-19 vaccination program was launched in Hong Kong in February 2021 (Table 1). Our previous serosurveillance studies showed that <1% of sera collected from the Hong Kong population before March 2021 tested positive for SARS-CoV-2 IgG, but the seropositive rate started to increase from April 2021 ^{30, 31}. In the current study, we first screened 1800 serum specimens collected between January and December 2021 with a surrogate virus neutralization test (sVNT), which has been shown to have a good correlation with conventional live virus neutralization test (cVNT) against the ancestral virus ²⁶. For sera tested positive by sVNT, we assessed the NAb against the ancestral virus and Omicron sublineages BA.1 and BA.2 using a cVNT. We interpreted our serosurveillance findings with the epidemiological and genomic information of the fifth wave of COVID-19 in Hong Kong, which exceeded 1 million cases by March 18, 2022 ³².

Sampled population

We retrieved a total of 1800 archived serum specimens collected between January and December 2021 from Queen Mary Hospital, with 300 serum specimens collected once every two months. We retrieved approximately the same number of serum specimens from each age group from 0-9 years old to ≥80 years old depending on availability (Supplementary Table S1).

COVID-19 vaccination in Hong Kong

The COVID-19 vaccination program was launched in Hong Kong in February, 2021 ³³ (Table 1). BNT162b2 and CoronaVac are the only vaccines available. Overall, 63.1% (4,662,005/7,394,700) of the population in Hong Kong has received the second dose of COVID-19 vaccines by December 31, 2021 (Figure 1A). The two-dose vaccination rate was highest for the 20-29 year-old age group (76.3%; 616,982/808700), and lowest for the ≥80 year-old age group (18.4%; 73,772/401,800) (Figure 1B-1J). The highest number of second-dose vaccination occurred in July/August, with a much lower number of people receiving the second dose in September/October and November/December (Supplementary Figure S1).

Overall, 63.0% (2,936,358 / 4,662,004) and 37.0% (1,725,646 / 4,662,004) received BNT162b2 and CoronaVac, respectively. However, the proportion of individuals receiving BNT162b2 was higher among the younger age groups than older age groups. For the 10-19 year-old age group, 94.0% (241,813 / 257,242) received BNT162b2, while there was a decreasing trend for older age groups (Figure 2). For the 80 years or above age group, only 35.1% (25,869 / 73,772) received the BNT162b2 vaccine.

Surrogate virus neutralization test

We first screened all 1800 serum specimens with a sVNT (iFlash-2019-nCoV NAb assay, YHLO), a competitive chemiluminescence immunoassay which measures antibodies that block the binding of ancestral virus receptor binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2). Previous studies showed good correlation between the results of this sVNT and cVNT against ancestral virus ^{34, 35}. The sVNT NAb result between January and April 2021 was reported previously ³⁰. Overall, there was an increase in the proportion of individuals tested positive in the sVNT in March/April after the launch of the COVID-19 vaccination program. The sVNT seropositive rate increased from 1.7% (5/300) in March/April to a peak of 34.3% (103/300) in September/October, with a slight decline to 30.3% (91/300) in November/December 2021 (Figure 1A). The geometric mean sVNT levels also peaked in September/October, and declined in all age groups in November/December except for the 10-19 year-old age group (Supplementary Figure S2).

Subgroup analysis of different age groups revealed stark differences in the positive rate in the sVNT among different age groups (Figure 1B-J). For sera collected from the 0-9 year-old individuals, who were not eligible for COVID-19 vaccines in 2021, all specimens tested negative in the sVNT (Figure 1B). For the 10-19 year-old age group, the seropositive rate rose sharply after July 2021, which coincided with the commencement of COVID-19 vaccination program for adolescents aged 12-17 years old on 14^th June 2021 (Figure 1C) ³⁶. In November/December, the 10-19 year-old age group had the highest sVNT seropositive rate, and there was a statistically significant trend towards lower seropositive rate for older age groups (age trend by Cochran-Armitage trend test: seropositive rate P<0.0001 for age groups between 30-39 and ≥80 years) (Figure 1K). Notably, none of the sera from the ≥80 year-old age group had tested positive in the sVNT in November/December. The 10-19 year-old age group also had the highest sVNT activity, and there was a statistically significant trend towards lower sVNT activity for older adults (P=0.0014; excluding the 0-9 year-old age group (Figure 3).

Conventional live virus neutralization tests

The commercial sVNT assay in this study was designed based on the ancestral virus. Our previous study showed that this assay has a high concordance with the result of cVNT NAb against the ancestral virus, but poor correlation with cVNT NAb against the Omicron sublineage BA.1 due to immune escape ²⁶. Hence, for specimens tested positive in the sVNT, we used a cVNT to determine the NAb activity against the Omicron sublineages BA.1 and BA.2 and the ancestral virus. Overall, 86.0% (227/264) of sVNT positive specimens had detectable NAb against the ancestral virus (Figure 1A). In contrast, only 7.2% (19/264) and 30.3% (80/264) had detectable NAb against BA.1 and BA.2, respectively. Live virus NAb against BA.1 was only found in sera from individuals between 10 and 69 years old, whereas live virus NAb activity against BA.2 could be found in sera from all age groups (Figure 1B-J). Assuming that all sVNT negative sera did not have detectable NAb against BA.1 or BA.2, the proportion of individuals with detectable NAb against BA.1 and BA.2 in November/December 2021 were 2.3% (7/300) and 7.3% (22/300), respectively.

The absence of seropositive sera in the 0-9 year-old age group, the temporal association of seropositive rate and two-dose vaccination rate, and the low incidence of locally acquired COVID-19 cases after April 2021, suggested that NAb were elicited by COVID-19 vaccination in most of the seropositive individuals in our population. While the two-dose vaccination rate and sVNT positive rates were very similar in the younger age groups, there was a greater discrepancy between the vaccination and sVNT seropositive rates in the older age groups (Figure 1). The greater discrepancy between vaccination and sVNT seropositive rates may be related to the lower proportion of individuals in the older age group receiving BNT162b2 (Figure 2), as the seropositive rate and antibody titer has been shown to be higher for BNT162b2 than CoronaVac ^{17, 37, 38, 39}.

The fifth wave of COVID-19 in Hong Kong

In Hong Kong, the fourth wave occurred between November 2020 and April 2021. Only five cases were reported between May 12 and October 8, 2021, and no locally acquired cases were reported between October 9 and Dec 30, 2021. The first local case of the fifth wave was reported on Dec 31, 2021. There was limited local transmission in January 2022 due to several Omicron variant-related clusters which could be traced to imported cases (n=836), including a BA.1 outbreak in a restaurant and a large Omicron BA.2 outbreak in a housing estate which we reported previously ^{40, 41} (Figure 4A). There was also a cluster of pet-store-related Delta variant AY.127 ⁴². Since early February, 2022, there was an exponential increase in cases from <200 cases per day before February 4 to a peak of 76,991 cases (56,827 confirmed by nucleic acid test and 20,164 confirmed by self-collected rapid antigen test on March 3, 2022 ^{43, 44}. As of March 24, 2022, there were 1,087,610 cases reported during the fifth wave. The age specific rate for COVID-19 hospitalization was highest among older adults (≥80 years: 0.62% [2,485/401,800]; 70-79 years old: 0.25% [1,381/560,500] and children (0-9 years old: 0.19%) [1,013/538,500] (Figure 4B). For the age groups from 10-59, the hospitalization rate was between 0.08-0.12%. The overall case-fatality rate was 0.60%, but the case-fatality rates were 15.3-fold and 2.4-fold higher for the ≥80 (9.19%) and 70-79 (1.46%) year-old age groups, respectively ⁴⁵ (Figure 4C).

Genomic epidemiology of the fifth wave from January to March 2022

We have previously reported our viral genome sequencing results for specimens collected up to February 2, 2022, including those from an Omicron BA.1 restaurant outbreak⁴¹, an Omicron BA.2 housing estate outbreak⁴⁰, and a Delta AY.127 outbreak related to pet stores⁴². Here, we have performed additional sequencing for specimens collected in Hong Kong up to March 11, 2022 (Supplementary Table S2).

In total, 545 specimens collected between December 1, 2021 and March 11, 2022, including 383 specimens collected during the fifth wave (on or after December 31, 2021), were analyzed in a time-resolved phylogenetic tree. During the fifth wave, 80.2% (307/383) of viral genome sequences belonged to Omicron sublineages BA.2 or related lineage (BA.2.2 or BA.2.3), 15.4% (59/383) belonged to Omicron sublineage BA.1 or related sublineages (BA.1.*), and 4.4% (17/383) belonged to Delta variant AY.127 (Figure 4D). Notably, all 127 viral genomes from specimens collected on or after February 12, 2022, belonged to the sublineages BA.2 or BA.2.2 (Supplementary Table S2), and the majority of (98.4%; 125/127) belonged to BA.2.2, which is characterized by the mutations C4893T (ORF1a T1543I), T10696C (synonymous), C12525T (ORF1a T4087I), and T25224C (Spike I1221T).

Serosurveillance is an effective tool that reveals the hidden burden of infection, especially during the beginning of the COVID-19 pandemic ³¹. In addition, serosurveillance using NAb assays is useful in assessing the level of protective immunity in a population. Our study found that although the cumulative two-dose vaccination uptake rate exceeded 60% in Hong Kong by November 2021, only 30% of our study population had a positive sVNT; and only 2.3% and 7.3% had detectable NAb against the Omicron sublineages BA.1 and BA.2, respectively. In particular, older adults had the lowest levels of protective immunity. None of the ≥80 year-old age group and only 12% of the 70-79 year-old age group had a positive sVNT, while none of the individuals ≥70 years old had detectable NAb against BA.1 or BA.2. The lack of protective immunity against the Omicron BA.2 sublineage, especially among older adults, likely contributed to the severe fifth wave in Hong Kong which exponentially increased in February 2022 and overwhelmed the healthcare system in Hong Kong ⁴⁶.

The sVNT seropositive rate was very similar to the two-dose cumulative vaccination rate among the 10-19 and 20-29 year-old age groups. However, we observed a greater discrepancy between two-dose vaccination rate and sVNT seropositive rate for older adults, which may be related to the weaker immune response in this age group. Previous studies showed that older adults have poorer antibody response after vaccination compared to younger adults. Saure et al showed that the IgG seropositive rate was lower among adults aged ≥60 years than those aged 18-39 years ²⁰. Wei et al showed that seropositivity after vaccination reduced faster for vaccine recipients aged over 75 years ¹⁵. Another possible reason for low seropositive rate among older adults is the vaccine preference among these age groups. Over 50% of adults aged ≥60 years have chosen CoronaVac. Head-to-head comparison showed that CoronaVac recipients had lower seropositive rates than BNT162b2 recipients ^{16, 17}. Furthermore, seropositive rate declined more rapidly for the CoronaVac than BNT162b2 recipients ²⁰. Our results support the World Health Organization’s recommendation that older adults should receive three doses of CoronaVac ⁴⁷.

The incidence of COVID-19 is very low in Hong Kong as a result of elimination strategy. Hence, the NAb detected by sVNT or cVNT for most individuals is likely elicited by vaccination rather than by infection. For the 0-9 year-old age group, none of the serum specimens tested positive in the sVNT, which is expected as the vaccination program for this age group was not yet started in 2021.

There was a decrease in seropositive rates in November/December. This coincided with a low vaccination update rate since September (Supplementary Figure S1), suggesting that there is waning of immunity. Our previous study showed that for natural infection, waning of NAb level occurs most rapidly in the first 4 months ²⁶. For vaccination, there is also evidence of waning immunity within the first few months ⁴⁸.

The spike protein of Omicron sublineage BA.2, especially the RBD, differs from that of BA.1. There were conflicting data regarding the difference in NAb titer against BA.1 and BA.2 for post-vaccine sera. In our previous study using serum from vaccine recipients or COVID-19 patients⁴⁹ and in this current study, we showed that BA.2 NAb titers were generally higher than those of BA.1. Iketani et al found that the NAb titers were similar between BA.1 and BA.2 ⁵⁰, while Yamashobe et al and Yu et al showed a slightly lower NAb titer against BA.2 ^{51, 52}. The difference may be related to the assay used. Both Yamashobe and Yu et al used pseudovirus assay, while our studies and those of Iketani et al used cVNT.

sVNT is a convenient assay which can be conducted in clinical or research laboratories without biosafety-level 3 facilities. sVNT is a competitive assay which measures antibodies that prevent the binding between SARS-CoV-2 RBD and the human receptor ACE2. Our previous study showed that sVNT has good correlation with the cVNT against the ancestral virus ²⁶. Our current study also showed a good correlation between sVNT and live virus NAb test against the ancestral virus for sVNT seropositive individuals. The sVNT can be easily modified to measure antibodies against the RBD of Omicron sublineages, and this would allow a more convenient assay for surveillance in the future.

There are several limitations in this study. First, as we are using anonymized serum specimens, we do not have clinical information or vaccination history from these individuals. Therefore, we are not able to perform further analysis to study factors that affect NAb response. In a population study conducted in UK, Wei et al showed that ethnicity, sex, social deprivation, and long term health conditions were associated with seropositivity after vaccination ¹⁵. Second, this study included hospital patients instead of the “general population”. Therefore, our data may not representative of people without comorbidities. However, those with underlying diseases would have a much greater risk of having severe disease, and therefore our estimate would be better in predicting the burden to the healthcare systems. Third, there were fewer specimens in the pediatric age groups as the volume of archived serum specimens were not sufficient for testing. Fourth, we did not test T cell immunity. Future studies are required to understand the relationship between population T cell immunity and susceptibility to infection.

Our study highlights the value of NAb surveillance in assessing population immunity. We demonstrated that the level of protective immunity, especially against antigenically distinct variants, may not be reliably predicted by vaccination history. The low level of protective immunity among older adults was associated with an exceptionally high case-fatality rate. Booster doses can improve the vaccine response, but it has been shown that waning of NAb also occurs after vaccine boosting ⁵³. Vaccine studies should put more focus on the older adults. Improving the immunogenicity among older adults should be a priority in vaccine research.

Patients

Anonymised archived serum samples from the clinical biochemistry laboratory of Queen Mary Hospital in Hong Kong were used for serological surveillance as we described previously ^{30, 31}. The archived specimens encompassed all age groups from 0-9 years old to ≥80 years old. A total of 300 serum specimens were randomly selected and tested in each two-month period from January/February to November/December 2021, with an approximately equal number of archived specimens in each 10-year age group depending on availability (Supplementary Table S1). Specimens were excluded if there was an insufficient volume of serum. Results of the surrogate NAb and live virus NAb against the ancestral virus for serum specimens collected between January and April 2021 was reported in our previous publication ³⁰, but the result of NAb against the Omicron sublineages BA.1 or BA.2 has not been reported before. For viral genome sequencing, 382 sequences were reported in our previous publications ^{40, 41, 42}. In the current study, we have performed genome sequencing for 163 randomly selected archived respiratory specimens collected from patients admitted to Queen Mary Hospital. This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 21-313 and UW 18–141). Written informed consent was waived since archived anonymized specimens were used.

Surrogate neutralization test and live virus neutralization test

sVNT test was performed using iFlash-2019-nCoV neutralization antibody assay according to manufacturer’s instructions (Shenzhen YHLO Biotech Co. Ltd., Shenzhen, China) ⁵⁴. The manufacturer’s cutoff for seropositivity is 15 AU/ml, while the maximum measurable result is 800 AU/ml.

cVNT was performed on VeroE6/TMPRSS2 cells (JCRB cell bank of Okayama University; Cat#JCRB1819). The cVNT NAb titer was determined by an end-point dilution and cytopathic effect as we described previously ^{17, 31}. Briefly, serum specimens were heat inactivated at 56°C for 30 min and were serially diluted in 2-folds with MEM containing 1% fetal calf serum (FBS) (Gibco). Duplicates of each diluted serum were mixed with 100 TCID₅₀ of an ancestral virus (GISAID accession number: EPI_ISL_434571), an Omicron sublineage BA.1 virus (GISAID accession number: EPI_ISL_7138045) ⁴⁹, an Omicron sublineage BA.2 virus (GISAID accession number: EPI_ISL_9845731) ⁴⁹ at 37°C for 1 hour. SARS-CoV-2 virus isolate to reach 100 TCID₅₀ final concentration and incubated at 37°C for 1 hour. After incubation, 100 mL of the serum-virus mixture was then added to VeroE6/TMPRSS2 cells that were seeded in 96-well plates 24 hours before infection. The cells were incubated with the mixture at 37°C. After incubation for 3 days, cytopathic effect was examined. The live virus neutralizing antibody titer was determined as the highest dilution with 50% inhibition of cytopathic effect. A live virus neutralizing antibody titer ≥10 was considered positive. For statistical analysis, a value of 5 was assigned if the live virus neutralizing antibody titer is <10.

Whole genome sequencing and genome data analysis

Whole genome sequencing was performed using the Oxford Nanopore MinION device (Oxford Nanopore Technologies) as we described previously ¹⁷. For the determination of viral lineage, nanopore sequencing was performed following the Nanopore protocol - PCR tiling of COVID-19 (Version: PTC_9096_v109_revH_06Feb2020) according to the manufacturer’s instructions with minor modifications (Oxford Nanopore Technologies) as we described previously ^{55, 56}. Briefly, extracted RNA was first reverse transcribed to cDNA using SuperScript^TM IV reverse transcriptase (ThermoFisher Scientific, Waltham, MA, USA). PCR amplification was then performed using the hCoV-2019/nCoV-2019 Version 3 Amplicon Set (Integrated DNA Technologies, Coralville, IA, USA) with the Q5® Hot Start High-Fidelity 2X Master Mix kit (New England Biolabs, Ipswich, Massachusetts, United States) according to the Nanopore protocol. PCR products were purified using 1x AMPure XP beads (Beckman Coulter, Brea, CA, USA) and quantified using Qubit dsDNA HS Assay Kit (Thermo Fisher Scientific, Waltham, Massachusetts, United States). The purified DNA was then normalized for end-prep and native barcode ligation reactions according to the PCR tiling of COVID-19 virus protocol with Native Barcoding Expansion 96 (EXP-NBD196, Oxford Nanopore Technologies). Barcoded libraries were then pooled, purified with 0.4x AMPure XP beads and then quantified using Qubit dsDNA HS Assay Kit. Purified pooled libraries were ligated to sequencing adapters and sequenced with the Oxford Nanopore MinION device using R9.4.1 flow cells for 24-48 hours.

For bioinformatics analysis, the recommended ARTIC bioinformatics workflow was used with minor modifications applied as described previously ^{55, 56}. The modifications include reducing the minimum length at the guppyplex step to 350 to allow potential small deletions to be detected and increasing the “–normalise” value to 999999 to incorporate all the sequenced reads and the high accurate mode was used for basecalling with an increased QC passing score from 7 to 10. The sequence NC_045512.2 obtained from NCBI was used as the reference and the alignment files produced by Medaka were inspected using Integrative Genomics Viewer (IGV) to verify the mutations called by the ARTIC pipeline. SARS-CoV-2 lineage were assigned using the PANGOLIN software suite ⁵⁷. All sequences are deposited onto the GISAID database (Supplementary Table S2).

Time-resolved phylogenetic tree

Time-resolved phylogenetic tree was constructed using TreeTime program as we described previously ⁵⁵. In addition to the described homoplastic position masking, we also removed the highly diverged sequences suggested by the TreeTime program. Sequences collected from December 1, 2021 to March 11, 2022 were aligned using MAFFT aligner. The maximum-likelihood whole genome phylogenetic tree construction and phylodynamic analysis were performed using IQ-TREE and TreeTime. For the construction of the phylogenetic tree, 100 standard nonparametric bootstrap replicates were used, and the option -czb was used to mask the unrelated substructure of the tree with branch length representing mutation count of less than 1. The resulting tree, sample collection date and the aligned sequences were used as an input for the treetime pipeline to create the phylodynamic tree. The outlier sequences (flagged by the treetime program) were removed when visualizing the tree.

Data for two-dose vaccination rate and COVID-19 outbreak in HK

The data for the two-dose vaccination uptake rate in Hong Kong was obtained from the Hong Kong government webpage ³³. The data of the Hong Kong population was obtained from Census and Statistics Department ⁵⁸.

Statistical analysis

Statistical analysis was performed using SPSS 26.0 (IBM SPSS Statistics) and GraphPad PRISM 9.1.1 (GraphPad Software, San Diego CA, USA). The Cochran-Armitage trend test was used to assess the age trend in the seropositive rate of neutralization test. The simple linear regression was used to assess the age trend in the sVNT titer. For the purpose of statistical analysis, an MN titer of <10 was considered as 5. A P value of <0.05 was considered statistically significant.

ACKNOWLEDGEMENT

This work was supported by Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (Ref no.: COVID190124), and donations of Richard Yu and Carol Yu, Shaw Foundation Hong Kong, Michael Seak-Kan Tong, May Tam Mak Mei Yin, Lee Wan Keung Charity Foundation Limited, Hong Kong Sanatorium & Hospital, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, the Jessie & George Ho Charitable Foundation, Kai Chong Tong, Tse Kam Ming Laurence, Foo Oi Foundation Limited, Betty Hing-Chu Lee, and Ping Cham So.

AUTHOR CONTRIBUTION

LLC and KKWT had roles in study design, data collection, data analysis, data interpretation, literature search and writing of the manuscript. LLC, SMUA, WMC, BPCC, JDI, AWHC, LL, XZ, YZ, WMC, AKWA, VCC, SS, KYY, KHC had roles in performing the experiments, data collection, data analysis, and/or data interpretation. All authors interpreted the data, revised the manuscript critically for important intellectual content and approved the final version of the manuscript.

COMPETING INTERESTS

All authors declare no conflicts of interest.

DATA AVAILABILITY

Genome sequences have been deposited into the GISAID database (Supplementary Table S2). Raw data for the neutralizing antibody assays are available upon reasonable requests.

1. Chan JF, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 395, 514-523 (2020).

2. To KK, et al. Lessons learned one year after SARS-CoV-2 emergence leading to COVID-19 pandemic. Emerg Microbes Infect, 1-89 (2021).

3. Li X, To KK, Yuen KY. Variants of SARS Coronavirus-2 and Their Potential Impact on the Future of the COVID-19 Pandemic. Zoonoses 1, DOI: 10.15212/ZOONOSES-12021-11003 (2021).

4. Collaborators C-MD. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet 398, 1700-1712 (2021).

5. Tso WWY, et al. Mental health & maltreatment risk of children with special educational needs during COVID-19. Child Abuse & Neglect, 105457 (2022).

6. Oliu-Barton M, et al. Elimination versus mitigation of SARS-CoV-2 in the presence of effective vaccines. Lancet Glob Health 10, e142-e147 (2022).

7. Lal A, Lim C, Almeida G, Fitzgerald J. Minimizing COVID-19 disruption: ensuring the supply of essential health products for health emergencies and routine health services. Lancet Reg Health Am, 100129 (2021).

8. To KK, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis 20, 565-574 (2020).

9. Tregoning JS, Flight KE, Higham SL, Wang Z, Pierce BF. Progress of the COVID-19 vaccine effort: viruses, vaccines and variants versus efficacy, effectiveness and escape. Nat Rev Immunol 21, 626-636 (2021).

10. Liu L, et al. High neutralizing antibody titer in intensive care unit patients with COVID-19. Emerg Microbes Infect 9, 1664-1670 (2020).

11. Brockman MA, et al. Reduced magnitude and durability of humoral immune responses to COVID-19 mRNA vaccines among older adults. J Infect Dis, (2021).

12. Kamar N, Abravanel F, Marion O, Couat C, Izopet J, Del Bello A. Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. N Engl J Med 385, 661-662 (2021).

13. Romero-Olmedo AJ, et al. Induction of robust cellular and humoral immunity against SARS-CoV-2 after a third dose of BNT162b2 vaccine in previously unresponsive older adults. Nat Microbiol, (2022).

14. Lui DTW, et al. A prospective study of the impact of glycaemic status on clinical outcomes and anti-SARS-CoV-2 antibody responses among patients with predominantly non-severe COVID-19. Diabetes Res Clin Pract 185, 109232 (2022).

15. Wei J, et al. Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general population of the United Kingdom. Nat Microbiol 6, 1140-1149 (2021).

16. Barin B, Kasap U, Selcuk F, Volkan E, Uluckan O. Comparison of SARS-CoV-2 anti-spike receptor binding domain IgG antibody responses after CoronaVac, BNT162b2, ChAdOx1 COVID-19 vaccines, and a single booster dose: a prospective, longitudinal population-based study. Lancet Microbe, (2022).

17. Lu L, et al. Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients. Clin Infect Dis, (2021).

18. Khoury DS, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med 27, 1205-1211 (2021).

19. Krause PR, et al. Considerations in boosting COVID-19 vaccine immune responses. Lancet 398, 1377-1380 (2021).

20. Saure D, O'Ryan M, Torres JP, Zuniga M, Santelices E, Basso LJ. Dynamic IgG seropositivity after rollout of CoronaVac and BNT162b2 COVID-19 vaccines in Chile: a sentinel surveillance study. Lancet Infect Dis 22, 56-63 (2022).

21. Tsang HW, et al. Assessment of SARS-CoV-2 Immunity in Convalescent Children and Adolescents. Front Immunol 12, 797919 (2021).

22. Peluso MJ, et al. SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay. Sci Adv 7, (2021).

23. Dan JM, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 371, (2021).

24. Tsang HW, et al. Assessment of SARS-CoV-2 Immunity in Convalescent Children and Adolescents. Front Immunol 12, 797919 (2021).

25. Thomas SJ, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months. N Engl J Med 385, 1761-1773 (2021).

26. Lu L, et al. Boosting of Serum Neutralizing Activity Against the Omicron Variant Among Recovered COVID-19 Patients by BNT162b2 and Coronavac Vaccines. Available at SSRN: https://ssrn.com/abstract=4029746 or http://dx.doi.org/10.2139/ssrn.4029746. (2022).

27. Feng S, et al. Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection. Nat Med 27, 2032-2040 (2021).

28. Gilbert PB, et al. Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial. Science 375, 43-50 (2022).

29. Lumley SF, et al. Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers. N Engl J Med 384, 533-540 (2021).

30. Li X, et al. High compliance to infection control measures prevented guest-to-staff transmission in COVID-19 quarantine hotels. J Infect, (2021).

31. To KK, et al. Seroprevalence of SARS-CoV-2 in Hong Kong Special Administrative Region and our returnees evacuated from Hubei province of China: a multi-cohort study. Lancet Microbe DOI:https://doi.org/10.1016/S2666-5247(20)30053-7, (2020).

32. Centre for Health Protection of the HKSAR government. Available at https://www.chp.gov.hk/files/pdf/local_situation_covid19_en_20220318.pdf. Accessed on 19th March 2022., (2022).

33. Food and Health Bureau THKSG. Daily count of vaccination by age groups. Available at https://data.gov.hk/en-data/dataset/hk-fhb-fhbcovid19-vaccination-rates-over-time-by-age. Accessed on January 25, 2022.

34. Tenbusch M, et al. Heterologous prime-boost vaccination with ChAdOx1 nCoV-19 and BNT162b2. Lancet Infect Dis 21, 1212-1213 (2021).

35. Chan KH, et al. Performance of a Surrogate SARS-CoV-2-Neutralizing Antibody Assay in Natural Infection and Vaccination Samples. Diagnostics (Basel) 11, (2021).

36. Chua GT, et al. Epidemiology of Acute Myocarditis/Pericarditis in Hong Kong Adolescents Following Comirnaty Vaccination. Clin Infect Dis, (2021).

37. Zhang R, et al. Antibody Response of BNT162b2 and CoronaVac Platforms in Recovered Individuals Previously Infected by COVID-19 against SARS-CoV-2 Wild Type and Delta Variant. Vaccines (Basel) 9, (2021).

38. Pérez-Then E, et al. Immunogenicity of heterologous BNT162b2 booster in fully vaccinated individuals with CoronaVac against SARS-CoV-2 variants Delta and Omicron: the Dominican Republic Experience. medRxiv, 2021.2012.2027.21268459 (2021).

39. Zhang R, et al. Correlation of Immunogenicity and Reactogenicity of BNT162b2 and CoronaVac SARS-CoV-2 Vaccines. mSphere, e0091521 (2022).

40. Cheng VC, et al. Rapid spread of SARS-CoV-2 Omicron subvariant BA.2 in a single-source community outbreak. Clin Infect Dis, (2022).

41. Cheng VC-C, et al. Outbreak investigation of airborne transmission of Omicron (B.1.1.529) - SARS-CoV-2 variant of concern in a restaurant: Implication for enhancement of indoor air dilution. J Hazard Mater 430, 128504 (2022).

42. Chan JF, et al. Probable Animal-to-Human Transmission of SARS-CoV-2 Delta Variant AY.127 Causing a Pet Shop-Related COVID-19 Outbreak in Hong Kong. Clin Infect Dis, (2022).

43. Center for Health Protection of the HKSAR Government. Latest situation of COVID-19 (as of 3 March 2022). Available at https://www.chp.gov.hk/files/pdf/local_situation_covid19_en_20220303.pdf. Accessed on March 17, 2022. (2022).

44. HKSAR Government Press Release. Rapid antigen tests report. Available at https://gia.info.gov.hk/general/202203/16/P2022031600720_389305_1_1647436589294.pdf. Accessed on March 17, 2022. (2022).

45. Centre for Health Protection of the HKSAR government. Latest situation of COVID-19 (as of 24 March 2022). Available at https://www.chp.gov.hk/files/pdf/local_situation_covid19_en_20220324.pdf. Accessed on March 25, 2022 (2022).

46. Science News Staff. East Asia sees COVID-19 explode. Available at https://www.science.org/content/article/news-glance-asia-s-covid-19-surge-melting-winter-sea-ice-and-inflammatory-arxiv-papers. Accessed on March 21, 2022. Science, (2022).

47. World Health Organization. The Sinovac-CoronaVac COVID-19 vaccine: What you need to know. Available at https://www.who.int/news-room/feature-stories/detail/the-sinovac-covid-19-vaccine-what-you-need-to-know?gclid=CjwKCAjwopWSBhB6EiwAjxmqDWmhxtDBuIGfl26BX6kM6M6qSVssnmG28YzZbWOPuAEZEQWixtVydRoCfA0QAvD_BwE. Accessed on April 1, 2022., (2021).

48. World Health Organization. COVID-19 Weekly Epidemiological Update Edition 82, published 8 March 2022. Available at https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-march-2022. Accessed on March 21, 2022. (2022).

49. Chen LL, Chu AW, Zhang RR, Hung IF, To KK. Serum neutralization of SARS-CoV-2 Omicron variant BA.2 among vaccine recipients or COVID-19 patients. Lancet Microbe, DOI:https://doi.org/10.1016/S2666-5247(1022)00060-X (2022).

50. Iketani S, et al. Antibody evasion properties of SARS-CoV-2 Omicron sublineages. Nature, (2022).

51. Yamasoba D, et al. Virological characteristics of SARS-CoV-2 BA.2 variant. bioRxiv, 2022.2002.2014.480335 (2022).

52. Yu J, et al. Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 Variants. N Engl J Med, (2022).

53. Chemaitelly H, et al. Duration of mRNA vaccine protection against SARS-CoV-2 Omicron BA.1 and BA.2 subvariants in Qatar. medRxiv, 2022.2003.2013.22272308 (2022).

54. Chan MMH, et al. Diagnostic Value of a SARS-CoV-2 Rapid Test Kit for Detection of Neutralizing Antibodies as a Point-of-Care Surveillance Test. Microbiol Spectr, e0099321 (2022).

55. Chan WM, et al. Phylogenomic analysis of COVID-19 summer and winter outbreaks in Hong Kong: An observational study. Lancet Reg Health West Pac 10, 100130 (2021).

56. To KK, et al. Unique Clusters of Severe Acute Respiratory Syndrome Coronavirus 2 Causing a Large Coronavirus Disease 2019 Outbreak in Hong Kong. Clin Infect Dis 73, 137-142 (2021).

57. GitHub. Cov-lineages/pangolin. Available at https://github.com/cov-lineages/pangolin. Accessed on 18th February 2022 (2022).

58. Census and Statistics Department HKSAR. Population Estimates. Table 1A: Population by Sex and Age Group. Available at https://www.censtatd.gov.hk/en/web_table.html?id=1A. Accessed on January 25, 2022.

Table 1. Timeline of COVID-19 vaccination program in Hong Kong

Date	Event
26^th February 2021	Administration of CoronaVac (Sinovac) vaccine officially started for adults aged 18 years or above
10^th March 2021	Administration of BNT162b2 (Pfizer-BioNTech) vaccine started for adults aged 18 years or above
14^th June 2021	Administration of BNT162b2 (Pfizer-BioNTech) vaccine started for adolescents aged 12 to 17 years old
2^nd December 2021	Administration of CoronaVac (Sinovac) vaccine started for adolescents aged 12-17 years old

There is NO Competing Interest.

SuppleTableS120220401.docx
Supplementary Table S1
SuppleTableS220220401.xlsx
Supplementary Table S2
SupplementaryFigureS1.tif
Supplementary Figure S1. Number of individuals with second dose of COVID-19 vaccine administered in each time period. Data were obtained from the website of the Food and Health Bureau of Hong Kong ³³.
SupplementaryFigureS2.tif
Supplementary Figure S2. The levels of neutralizing antibody in the surrogate virus neutralization test. (A-I) The levels of neutralizing antibody in different age groups. The geometric mean level is shown in the horizontal bar. Dotted horizontal lines represent the manufacturer’s seropositivity cutoff level (15 AU/ml).

Download PDF

Journal Publication

published 24 Jun, 2022

Read the published version in Nature Communications →

Version 1

posted

You are reading this latest preprint version

Contribution of low population immunity to the severe Omicron BA.2 outbreak in Hong Kong

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Results

Discussions

Methods

Declarations

References

table

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1