﻿Effectiveness of heterologous 3rd and 4th dose COVID-19 vaccine schedules for SARS-CoV-2 infection during delta and omicron predominance in Thailand.

doi:10.21203/rs.3.rs-1792139/v1

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Research Article

Effectiveness of heterologous 3^rd and 4^th dose COVID-19 vaccine schedules for SARS-CoV-2 infection during delta and omicron predominance in Thailand.

https://doi.org/10.21203/rs.3.rs-1792139/v1

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The Coronavirus disease 2019 (COVID-19) pandemic has evolved quickly, with numerous waves of different variants of concern resulting in substantial morbidity and mortality globally. With the rapid availability of vaccines, Thailand has responded with a robust campaign to protect those at highest risk first, followed by population level protection. To ensure adequate vaccination coverage, agility was required, and Thailand has proactively adopted heterologous vaccination schedules to manage vaccine availability. While randomised controlled trials have assessed homologous schedules in detail, limited data has been reported for heterologous vaccine effectiveness (VE). Utilising a unique active surveillance network established in Chiang Mai, Northern Thailand, we conducted a test-negative case control study to assess the vaccine effectiveness of heterologous third and fourth dose schedules against SARS-CoV-2 infection during delta-predominant and omicron predominant periods. We noted very high effectiveness against delta infection after the third dose (adjusted VE 97%, 95% CI 94–99%) in comparison to moderate protection against omicron infection after a third dose (adjusted VE 31%, 95% CI 26–36%) and good protection after a fourth dose (adjusted VE 75%, 95% CI 71–80%). VE was consistent across age groups for both delta and omicron infection. The VE of third or fourth vaccine doses against omicron infection were equivalent for the three main vaccines used for boosting in Thailand suggesting coverage, rather than vaccine type is a much stronger predictor of protection. Additionally, a separate evaluation of a hospital patient management system noted extremely high effectiveness against severe COVID-19 and mortality outcomes after the third and fourth doses. Our data suggests that a fourth vaccination dose has a high probability of preventing infection and a very high probability of preventing death and severe COVID-19. This is critically important in preventing severity and unnecessary deaths but will also help to support the ongoing efforts to increase population coverage of booster doses.

Infectious Diseases

Effectiveness of heterologous vaccines

As of June 1^st 2022, the Coronavirus disease 2019 (covid-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 530 million confirmed cases globally with more than 150 million in Asia and almost 4.5 million in Thailand alone.¹This has unfortunately resulted in almost 6.3 million deaths worldwide, with almost 1.5 million deaths across Asia and over 30,000 in Thailand.¹This has created an enormous burden on healthcare, on people and on the economy.^2,3 While public health measures like wearing of masks, social distancing and appropriate hygiene measures were able to limit the spread of SARS-CoV-2, it was the rapid development and deployment of vaccines which reduced the impact of COVID-19 substantially.^4,5

WHO has licensed 11 COVID-19 vaccines to date and globally almost 12 billion doses have been administered.⁶While these vaccines have had an enormous impact in countries that have achieved high coverage rates, as at 22 May 2022, only 57 countries have vaccinated 70% of their population and almost one billion people in lower-income countries remain unvaccinated.⁷ There are six approved COVID-19 vaccines in Thailand⁸ and a sustained effort by the government has resulted in 75.7% of the population being fully vaccinated (2 doses) and an additional 40.7% receiving three doses or above as of 31^st May 2022.^{1 ,9}

Randomised controlled clinical trials demonstrated a number of COVID-19 vaccines to be safe and immunogenic in homologous schedules, with high efficacy against both symptomatic infection and severe outcomes such as hospitalisation and death. This enabled the rapid emergency use authorisation and initial rollout of the first of these in Thailand, CoronaVac (Sinovac) in March 2021¹⁰ChAdOx1 (AstraZeneca) in June 2021¹¹and BNT162b2 (Pfizer-BioNTech) in October 2021.¹²

Subsequently, the majority of the initial primary series vaccinations in Thailand were given as 2 doses of CoronaVac for people aged 18-59 years old or 2 doses of ChAdOx1 for those who aged 60 or above. During vaccine rollout, people living with chronic medical conditions such as coronary artery disease, chronic kidney disease, cancer patients on chemotherapy, were prioritised. With the arrival of BNT162b2, doses were initially targeted to younger age groups (>12 years). Due to challenges in vaccine supply and to manage public concerns around the effectiveness and duration of CoronaVac, heterologous schedules were implemented in November 2021 including 3^rd dose (boosters) with ChAdOx1 and BNT162b2. Small number of 4^th doses (second booster) were administered to high-risk individuals throughout Q4 2021 but were implemented more widely beginning in January 2022, using BNT162b2, ChAdOx1 and Spikevax (Moderna) in part to address additional concerns around potential immune escape by the omicron variant. The majority of 4^th doses vaccines in Thailand have been administered to individuals receiving a 2 dose CoronaVac primary series. The initial global clinical trials evaluated efficacy against early variants of concern, using homologous schedules, and high and equivalent effectiveness has been observed by the most widely used vaccines in real world studies, especially against severe COVID-19 outcomes.¹³ Some studies have reported higher neutralizing-antibody response with heterologous boosters as compared to homologous boosters.^14-16 However, there is limited data available on the real-world vaccine effectiveness (VE) of heterologous schedules, particularly against the newer omicron variants.^17,18 Reports of waning antibody titers and protection against infections, particularly with the Omicron variant(s) have driven the rollout of booster doses globally so it is critical to evaluate the impact these additional doses have as soon as possible. This becomes even more relevant for Asian countries where heterologous schedules have been used very widely.

The current study draws on a unique active surveillance network¹⁹ established in Chiang Mai, located in Northern Thailand, with a population of 1.6 million. The comprehensive system allows serial assessment of VE for SARS-CoV-2 infection of heterologous schedules during delta-predominant and omicron predominant periods in the same population.Additionally, a preliminary evaluation of a hospital patient management system provides a descriptive analysis of the impact of 3^rd and 4^th booster doses against COVID-19 severity and mortality outcomes.

Study Objectives:

Primary objectives of the study were:

To evaluate the effectiveness of heterologous three dose COVID-19 vaccine schedules for SARS-CoV-2 infection during delta predominant period.
To evaluate the effectiveness of heterologous three dose and four dose COVID-19 vaccine schedules for SARS-CoV-2 infection during omicron predominant period.

Study population:

Residents of Chiang Mai, Thailand, aged 18 years or older, presenting to any community-based testing facilities for a SARS-CoV-2 test between 1 Oct 2021 – 31 Dec 2021 (Delta-predominant) and 1 Feb 2022 – 10 Apr 2022 (Omicron- predominant) were assessed for eligibility to be included in the study. Molecular testing revealed 96.5% delta and 95.6% omicron lineage during 1 Oct 2021 – 31 Dec 2021 and 1 Feb 2022 – 10 Apr 2022 periods respectively. Tests done in Jan 2022 were excluded due to mixed delta-omicron lineage among samples (Omicron 75%, Delta 25%). The data capture ended on 10 April 2022 which was the last date community testing facilities were operational in Chiang Mai, before largely shifting to self-testing.

Subjects were included if they were either close-contacts of COVID-19 cases or attended an event where a COVID-19 outbreak was detected, irrespective of occurrence of symptoms. Those without history of exposure to COVID-19 were excluded. Non-Thai residents (foreigners and migrants) were excluded as the vaccination and other data for this group may be incomplete.

The patient selection flow is presented under Figures 1a and 1b.

Data Sources:

We have previously published the details on creating and implementing the different information systems used in this study.¹⁹Brief descriptions of the data sources are outlined below.

Surveillance System (Epid-CM platform) and COVID-19 case management system in Chiang Mai (CMC-19 platform):

COVID-19 cases were reported in the surveillance system of Chiang Mai Provincial Health Office. According to Communicable Disease Control Act (B.E. 2558), all COVID-19 cases must be reported from every public and private health facilities in the province. Epid-CM, the web-based reporting system of COVID-19 cases in Chiang Mai was created by Chiang Mai Provincial Health Office and Faculty of Public Health of Chiang Mai University since April 2021. After detection of COVID-19 case, the patient details, clinical manifestations, history of exposure with COVID-19 cases or suspected outbreak, laboratory testing method and result were entered into the system under a unique ID for each patient. Epid-CM is synchronized with Chiang Mai hospital management platform for COVID-19 (CMC-19) for bed management in the overall province. Classification of severity was evaluated and entered into CMC-19 by the attending clinical team. Asymptomatic or mild cases were treated as out-patient and isolated in designated place in community, community-isolation, or home-isolation since the beginning of Omicron variant spread throughout Chiang Mai in Jan 2022. Data on progression of the disease and treatments are recorded in each hospital information system. Death cases are reported to Chiang Mai Provincial Health Office and also recorded in Epid-CM.

Community-based testing sites were initiated in the city of Chiang Mai, where most of the cases were located since April 2021, and provided free of charge COVID-19 tests. Those tested included close contacts of COVID-19 cases, those who attended an event with a COVID-19 outbreak, or those who have developed suggestive respiratory symptoms, i.e., fever, cough, rhinorrhea, anosmia, dyspnea. Health personnel perform either RT-PCR testing (mainly November 2021 to January 2022) or antigen testing (February 2022 onwards), and note down test details and results for all cases in Epid-CM.

Ministry of Public Health Immunization Center (MOPH IC) database:

All national vaccination records are deposited in the “Morprom” application, which was launched by the Ministry of Public Health, Thailand. This allows the residents to access vaccination services, including vaccine reservation and tracking as well as updated information on COVID-19. It also includes a feature that enables post-vaccination monitoring to check for side effects.

Ethical considerations:

The study was conducted on routine data collected as part of the national COVID-19 response under the Communicable Disease ACT (B.E. 2558) and was exempted from ethics review. Data were de-identified at source and analysed by Chiang Mai Provincial Health Office and Faculty of Public Health, Chiang Mai University.

Study Design:

A test-negative, case-control analysis was conducted to estimate VE against SARS-CoV-2 infection. Separate analyses were done for delta-predominant and omicron predominant periods. Cases were defined as those with a positive SARS-CoV-2 result, and controls were those with negative SARS-CoV-2 result, either by RT-PCR or medically administered antigen testing.

The type of COVID-19 vaccine, and date of vaccination were extracted from MOPH-IC. For the primary analysis, subjects who received their COVID-19 vaccination within 14 days of the test date were excluded to allow time for adequate immune responses to develop. Additionally, we explored the data incorporating subjects vaccinated less than 14 days but after 7 days prior to inclusion.

Statistical Analysis:

Descriptive statistics are reported separately for the cases and controls, stratified by delta and omicron predominance. Continuous variables are summarized as mean and standard deviation (SD) or median and interquartile range (IQR) depending on the distribution. Categorical variables are summarized as frequency and percentages. Between group comparisons were done using Mann-Whitney-U test or Kruskal Wallis test for continuous variables and Chi-squared test for categorical variables.

Associations between SARS-CoV-2 infection and heterologous vaccination schedule were estimated by comparing the odds of vaccination (exposed) vs no vaccination (unexposed) separately for delta and omicron predominant periods. The OR was used to estimate VE, where VE = (1 – OR) × 100% with 95% Confidence Interval (CI). Separate VEs were calculated for different vaccination schedules and stratified by age group. Forest plots were used to visualise the VEs.

Logistic regression models were used to adjusted for age, gender, calendar day of test (in weekly units), to calculate adjusted OR for SARS-CoV-2 infection separately for delta and omicron predominant periods. Primary vaccination series type, type of last vaccination received, and time since last vaccine dose were examined as separate factors in the model. Interaction terms were explored as appropriate. VE was estimated using adjusted ORs.

In addition to the test-negative case control study described above, we analysed data from the COVID-19 patient management program, which is a hospital patient management system, to examine the association between mortality and vaccination schedules.

All statistical analyses were conducted using stata (version 15.0 SE, College station, TX:StataCorp LP). Significance tests were 2 sided and a p-values <0.05 were considered statistically significant.

Population demographics

There were 19,235 COVID-19 cases and 156 deaths during the delta predominant period (1 October 2021 to 31 December 2021), and 296,064 COVID-19 cases and 175 deaths during the Omicron predominant period (1 Feb 2022 to 10 Apr 2022), in Chiang Mai province. For the primary analysis of the association of vaccination with SARS-CoV-2 infection in adults, a total of 27,301 subjects (2,130 cases and 25,171 controls) were included during the delta predominant period and 36,170 subjects (14,682 cases and 21,4881 controls) were included during the period omicron predominant period (Figures 1a&1b, Tables 1a&1b).

During the delta period, cases and controls were of similar ages (40 and 39 years, respectively), while during the omicron period, cases were slightly younger than controls (34 and 37 years, respectively), primarily due to a higher proportion of 18-29 year olds identified as cases during this period. In both periods, subjects who received boosters were significantly older as compared to those who received only one or two doses. In the omicron period, subjects who received four doses were more likely to be in 30-59 age group , while those who received three doses were more likely to be in 60-69 age group. (Tables 2a&2b). This is reflective of the vaccine roll out in Thailand, where <60-year-olds received their first doses earlier from April 2021, while those >60 years mostly received their first dose within Jun 2021. No fourth doses were observed in the study population during the delta period. A slightly higher proportion of females were included in both periods and overall, proportions were relatively consistent across doses with the exception of a higher proportion of males being unvaccinated during the delta period or only having had only 1 dose during omicron (Tables 2a&2b).

Multiple different schedules of vaccines were used for the primary schedule and vaccine use varied between the two periods. Overall, controls were more likely to have received vaccinations, with less cases completing their primary series (2 doses) or 3^rd or 4^th doses, and cases had significantly longer median intervals than controls since their last vaccinations during the omicron period for their 2^nd dose (117 vs 104 days), 3^rd dose (58 vs 50 days) and 4^th dose (44 vs 39 days) (Table 1b). Notably during the delta period among 1,197 subjects receiving 3^rd doses, only 5 (0.4%) were cases (Table 1a). During the omicron period, amongst 12,366 subjects with recorded third dose vaccinations, approximately 46% received Pfizer-BioNTech, 35% received ChAdOx1 (AstraZeneca), 18% received Moderna and less than 0.5% received SV. For the 823 subjects with a recorded 4^th dose in the omicron period, approx. 50% received Pfizer-BioNTech, 44% received Moderna and approx. 6% received ChAdOx1 (AstraZeneca) (Table 1b).

Vaccine effectiveness

Effectiveness against delta infection was minimal after only one dose. After adjusting for age, gender and calendar week of test, a two dose primary vaccine series had a VE of 63% (95%CI 59-67%) against delta while a third dose increased the VE to 97% (95%CI 94-99%) (Fig 2a, Supplementary Table 1a). The VE against delta was consistent across different age groups for both two or three doses. (Fig 2a)

During the omicron period, when combining all vaccine types compared to unvaccinated subjects, one or two doses of vaccine provided little to no protection against omicron infection while adjusted VE for a three dose vaccine series was 31% (95%CI 26-36%) and a four dose vaccine series was 75% (95%CI 71-80%) (Fig 2b, Supplementary Table 1b). Three or four dose VE against omicron was consistent across 18-50 year age groups but limited case numbers prevents accurate assessment of older ages.

Due to the very small numbers of cases observed, only the VE for ChAdOx1 (AstraZeneca) vaccine as a third dose in delta period could be calculated with an adjusted VE of 93% (95% CI 82-97) against delta infection (Supplementary Table 1a). During the omicron period, adjusted VE for the effectiveness of the third dose did not differ significantly by type of vaccine for the three main vaccines used in Chiang Mai (26-31%) (Fig 3b, Supplementary Table 1b). Similarly, adjusted VE for the effectiveness of the fourth dose also did not differ significantly by type of vaccine (71-73%) (Fig 3b, Supplementary Table 1b).

For all analyses, adjusting the exclusion criteria to include those vaccinated >7 days since vaccination resulted in broadly similar observations (data not shown).

A separate preliminary analysis of vaccine effectiveness against severe COVID-19 (requiring invasive mechanical ventilation (IMV) support) and COVID-19 mortality using hospital databases in Chiang Mai during the Omicron wave in February and March demonstrated very high VE against both outcomes (data not shown). Interestingly, two doses provided 74% and 86% protection against IMV or death in 18-59 year olds and >60 year olds, respectively, demonstrating much greater protection against severe outcomes due to omicron than we observe against overall infection. Three doses of vaccines administered at least 14 days earlier provided 96% (95% CI 67-99) protection in 18-59 year olds and 97% (95% CI 92-99) protection in >60 year olds against death. Against either IMV or death three doses provided 98% protection while as of 15^th June 2022, we have observed only a single COVID-19 death reported following a fourth dose in a person with comorbidities (56 year old with hypertension, heart disease and high cholesterol) suggesting very high effectiveness. Analysis of this dataset is ongoing and will be reported elsewhere.

While the number of COVID-19 cases and deaths globally is unacceptably high, the impact of vaccinations is undisputable, when they have been implemented appropriately. As vaccination schedules have rapidly evolved to 3^rd and 4^th doses in an attempt to manage new variants and concerns around waning immunity, the availability of data to support decision makers has struggled to keep pace. The current study provides urgently needed data to support the continued rollout of 3^rd dose schedules in Thailand and Asia and for the first time provides vaccine effectiveness data for 4^th dose schedules incorporating inactivated vaccines into the primary series. Our results confirm data from other groups that VE against infection by the omicron variant is consistently lower than for the delta variant.^18,20 Our data is highly consistent with a recent study from Bangkok in Thailand evaluating 3^rd dose schedules against the delta variant.²¹ In that study, the adjusted VE among individuals who received two and three doses of the vaccines was 65% (95% CI, 56–72), and 91% (95% CI, 84–95), respectively during the delta predominant period. This compares well with what we observed, 63% for two doses, 97% for three doses. Studies have demonstrated that 2 doses of vaccine provides little to no protection against omicron infection and only mild protection against more severe outcomes.²⁰ We also see this in our dataset with minimal protection against omicron infection evident after one or two doses. We see moderate protection against omicron infection after a third dose (30-40%) and good protection (>70%) after a fourth dose. VE against omicron infection was also quite consistent irrespective of age. Importantly, the VE of third or fourth vaccine doses against omicron infection were equivalent for the three main vaccines used for boosting in Thailand. Although the current study did not have sufficient events to compare VE of third dose against delta by vaccine type, the recent publication by Sritipsukho et al, found comparable protection from a third dose of ChAdOx1 and BNT162b2.²¹ Together, this data strongly suggests that accelerating the third and fourth dose vaccinations and increasing coverage by using any vaccines available, particularly among those aged 60 and older or those with co-morbidities is a valid strategy. Vaccination in addition to using personal protection measures such as wearing a mask, social distancing, and avoiding crowded settings, can help to reduce omicron strain outbreaks and, more importantly, mortality in the elderly or those with co-morbidities.

While the primary analysis of our dataset evaluated VE against infection, we also observe VE against severe COVID-19 outcomes is extremely high after the 3^rd and 4^th doses. Our data suggests that a fourth vaccination dose has a high probability of preventing infection and a very high probability of preventing death and IMV with only one COVID-19 death recorded among 4^th dose recipients in Chiang Mai Province to date and this was in a person with significant risk factors. This is critically important in preventing severity and unnecessary deaths but will also help to support the ongoing efforts to increase population coverage of booster doses. The equivalent VE observed for the main booster vaccines used in Thailand is consistent with a recent global analysis of VE data demonstrating equivalence of mRNA and vector vaccines as two dose schedules against earlier variants of concern.¹³

Strengths and Limitations:

The subjects included in the study were close contacts of a COVID-19 case, who may or may not have presented with symptoms suggestive of COVID-19. This may have some impact on the generalisability of results, ie. results are generalisable to the household/close contacts seeking testing rather than symptomatic individuals seeking testing. In addition to age, gender and calendar time other baseline confounders such as socioeconomic status, comorbidities and prior COVID-19 infection were not examined in this analysis.

The strengths of the study include the use of harmonised databases with complete record capture for vaccination status. The community based testing sites provided facilities for people who stayed in the city and surrounding 6 districts where around 40-50% of the COVID-19 cases were reported, and is therefore largely representative of the resident population.

The current study provides urgently needed data to support the administration of additional doses of COVID-19 vaccines. Despite the high effectiveness observed for all vaccine booster schedules evaluated here, coverage rates in Thailand and in most of the world, are much lower than needed, particularly among the elderly and higher risk segments of the population. Maintaining high vaccination coverage is important in the face of new variants of concern and waning immunity over time. As the pandemic evolves and COVID-19 is eventually declared an endemic disease complacency will likely increase and it may be difficult for governments to continue to support a strong emphasis on preventative measures. As a result, having a high coverage of third booster vaccinations (targeting 60 percent by Jun 2022) in Thailand is projected to play a crucial role in decreasing mortality for those aged 60 and above and those with comorbidities to and preventing infection in the future. According to local recommendations, it should be considered for boosting the fourth immunization dose after four months following the third dose, as well as for people above 60 years of age or those with comorbidities. Our data supports the use of ChAdOx1 (AstraZeneca), Pfizer-BioNTech and Moderna as booster vaccines, providing much needed flexibility to incorporate different vaccines into schedules according to local supply and logistical considerations.

Acknowledgements:

This research was supported by the National Research Council of Thailand (NRCT) under The Smart Emergency Care Services Integration (SECSI) project to Faculty of Public Health Chiang Mai University. We are grateful to the Chiang Mai Provincial Health Office and the Department of Disease Control Ministry of Public Health for the collaborative partnerships in managing health information of COVID-19 epidemic.

Competing interests: The authors declare no competing interests.

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Table 1a. Characteristics of subjects included in Analysis of Association of vaccination With SARS-CoV-2 Infection In Adults, during Delta predominance (1 Oct 2021- 31 Dec 2021)

	Total (N=27301)	SARS-CoV-2 status
Variable		Negative (Controls)	Positive (Cases)	*p-value*
Number (%)		25171 (92.2)	2130 (7.8)	-
Age, years
Mean (SD)	39 (14)	39 (14)	40 (16)
Median (IQR)	37 (28, 49)	37 (28,49)	37 (26,50)	0.36
Age group, n (%)
18-29	8202 (30.0)	7491 (29.7)	711 (33.4)	<0.01
30-39	7147 (26.2)	6667 (26.5)	480 (22.5)
40-49	5334 (19.5)	4948 (19.7)	386 (18.1)
50-59	3707 (13.6)	3465 (13.8)	242 (11.4)
60-69	2097 (7.7)	1905 (7.6)	192 (9.0)
≥70-	814 (2.9)	695 (2.7)	119 (5.6)
Gender, n (%)
Male	12745 (46.7)	11693 (46.5)	1052 (49.4)	<0.01
Female	14556 (53.3)	13478 (53.6)	1078 (50.6)	<0.01
Vaccination Status, n (%)
Unvaccinated	9697 (35.5)	8570 (34.0)	1127 (52.9)	<0.01
Vaccinated One dose only	3360 (12.3)	3001 (11.9)	359 (16.9)
Vaccinated two doses only	13045 (47.8)	12406 (49.3)	639 (30.0)
Vaccinated three doses	1199 (4.4)	1194 (4.7)	5 (0.2)
Type of primary vaccine series (n=13045), n (%)
SV/SP-AZ	6609 (50.7)	6333 (51.1)	276 (43.2)	na
SV-SV or SP-SP	4770 (36.6)	4485 (36.1)	285 (44.6)
AZ-AZ	1326 (10.2)	1251 (10.1)	75 (11.7)
PFZ-PFZ	194 (1.5)	191 (1.5)	3 (0.5)
AZ-PFZ/Mod	133 (1.0)	133 (1.1)	0
SV/SP-PFZ/Mod	11 (0.1)	11 (0.1)	0
Mod-Mod	2 (0.02)	2 (0.02)	0
Type of third vaccine dose (n=1197)¹, n (%)
PFZ	210 (17.6)	210 (17.6)	0	0.40
AZ	879 (73.4)	874 (73.3)	5 (100)
Mod	108 (9.0)	108 (9.1)	0
Median (IQR) time since last vaccination,²days	53 (28,84)	53 (28,84)	48 (29,79)	0.22
Median (IQR) time since last vaccination (two doses only)³	53 (32,79)	53 (32,79)	49 (30,74)	0.35
Vaccination coverage
Completed primary vaccine series, n (%)	14244 (52.2)	13600 (54.0)	644 (30.2)	<0.01
Completed third vaccine dose, n (%)	1199 (4.4)	1194 (4.7)	5 (0.2)	<0.01

SV=CoronaVac (Sinovac), SP=Sinopharm, AZ=ChAdOx1 (AstraZeneca),PFZ=BNT162b2 (Pfizer-BioNTech), Mod=Spikevax (Moderna)

¹ Vaccine type missing in 2 (0.02%)

² Date of last vaccination missing in 258 (1.5%)

³ Date of last vaccination missing in 96 (0.7%%)

Table 1b. Characteristics of subjects included in Analysis of Association of vaccination With SARS-CoV-2 Infection In Adults, during Omicron predominance (1 Feb 2022-10 Apr 2022)

	Total (N=36170)	SARS-CoV-2 status
Variable		Negative (Controls)	Positive (Cases)	*p-value*
Number (%)		214881 (59.4)	14682 (40.6)	-
Age, years
Mean (SD)	36 (14)	37 (14)	34 (14)
Median (IQR)	33 (24,46)	35 (25,47)	31 (23,44)	<0.01
Age group, n (%)
18-29	14981 (41.42)	8107 (37.7)	6874 (46.8)	<0.01
30-39	7712 (21.3)	4732 (22.0)	2980 (20.3)
40-49	6276 (17.3)	4034 (18.7)	2242 (15.3)
50-59	4125 (11.4)	2686 (12.5)	1439 (9.8)
60-69	2340 (6.5)	1471 (6.8)	869 (5.9)
≥70	736 (2.0)	458 (2.1)	278 (1.9)
Gender, n (%)
Male	16783 (46.4)	10011 (46.6)	6772 (46.1)	0.38
Female	19387 (53.6)	11477 (53.4)	7910 (53.9)	0.38
Vaccination Status, n (%)
Unvaccinated	4610 (12.7)	2681 (12.5)	1929 (13.1)	<0.01
Vaccinated One dose only	470 (1.3)	272 (1.3)	198 (1.3)
Vaccinated two doses only	17897 (49.5)	9934 (46.2)	7963 (54.2)
Vaccinated three doses only	12369 (34.2)	7950 (37.0)	4419 (30.1)
Vaccinated four doses	824 (2.3)	651 (3.0)	173 (1.2)
Type of primary vaccine series (n=17893)¹, n (%)
SV/SP-AZ	7780 (43.5)	4464 (44.9)	3316 (41.7)	<0.01
AZ-PFZ/Mod	3661 (20.5)	1904 (19.2)	1757 (22.1)
SV-SV or SP-SP	3080 (17.2)	1713 (17.2)	1367 (17.2)
PFZ-PFZ	2340 (13.1)	1237 (12.5)	1103 (13.9)
Mod-Mod	516 (2.9)	294 (2.9)	222 (2.8)
AZ-AZ	396 (2.2)	249 (2.5)	147 (1.9)
SV/SP-PFZ/Mod	120 (0.7)	72 (0.7)	48 (0.6)
Type of third vaccine dose (n=12366)², n (%)
PFZ	5700 (46.1)	3670 (46.2)	2030 (45.9)	0.50
AZ	4418 (35.7)	2874 (36.2)	1544 (35.0)
Mod	2212 (17.9)	1378 (17.3)	834 (18.9)
SV/SP	36 (0.29)	28 (0.3)	8 (0.2)
Type of fourth vaccine dose (n=823)³, n (%)
Mod	356 (43.3)	278 (42.7)	78 (45.4)	0.68
PFZ	414 (50.3)	329 (50.5)	85 (49.4)
AZ	53 (6.4)	44 (6.7)	9 (5.2)
Median (IQR) time since last vaccination⁴, days	85 (53,122)	80 (48,112)	93 (61,137)	<0.01
Median (IQR) time since last vaccination (two doses only)	110 (84,150)	104 (81,140)	117 (89,167)	<0.01
Median (IQR) time since last vaccination (three doses only)	53 (35,75)	50 (32,74)	58 (40,77)	<0.01
Median (IQR) time since last vaccination (four doses)	40 (26,57)	39 (26,56)	44 (27,62)	0.06
Vaccination coverage
Completed primary vaccine series, n (%)	31090 (85.9)	18535 (86.3)	12555 (85.5)	0.04
Completed third vaccine dose, n (%)	13193 (36.5)	8601 (40.0)	4592 (31.3)	<0.01
Completed fourth vaccine dose, n (%)	824 (2.3)	651 (3.0)	173 (1.2)	<0.01

SV=CoronaVac (Sinovac), SP=Sinopharm, AZ=ChAdOx1 (AstraZeneca),PFZ=BNT162b2 (Pfizer-BioNTech), Mod=Spikevax (Moderna)

¹ Vaccine type missing in 4 (0.02%)

² Vaccine type missing in 3 (0.02%)

³ Vaccine type missing in 1 (0.12%)

⁴ Among 31299 who received at least 1 dose and dates of vaccination available

Table 2a. Characteristics of subjects by vaccination status at inclusion during Delta predominance (1 Oct 2021- 31 Dec 2021)

	Total (N=27301)	Vaccination status
Variable		Unvaccinated	Vaccinated One dose only	Vaccinated two doses only	Vaccinated three doses	*p-value*
Number (%)		9697 (35.5)	3360 (12.3)	13045 (47.8)	1199 (4.4)	-
Age, years Median (IQR)	37 (28, 49)	35 (27,47)	36 (26,48)	39 (29,51)	39 (31,48)	<0.01
Age group, n (%)
18-29	8202 (30.0)	3383 (34.9)	1204 (35.8)	3379 (25.9)	236 (19.7)	<0.01
30-39	7147 (26.2)	2483 (25.6)	809 (24.1)	3465 (26.6)	390 (32.5)
40-49	5334 (19.5)	1778 (18.3)	585 (17.4)	2641 (20.2)	330 (27.5)
50-59	3707 (13.6)	1154 (11.9)	465 (13.8)	1876 (14.4)	212 (17.7)
60-69	2097 (7.7)	605 (6.2)	229 (6.8)	1235 (9.5)	28 (2.3)
≥70	814 (2.9)	294 (3.0)	68 (2.0)	449 (3.4)	3 (0.3)
Gender, n (%)
Male	12745 (46.7)	4942 (50.9)	1533 (45.6)	5737 (43.9)	533 (44.5)	<0.01
Female	14556 (53.3)	4755 (49.0)	1827 (54.4)	7308 (56.0)	666 (55.6)	<0.01

Table 2b. Characteristics of subjects by vaccination status at inclusion during Omicron predominance (1 Feb 2022-10 Apr 2022)

	Total (N=36170)	Vaccination status
Variable		Unvaccinated	Vaccinated One dose only	Vaccinated two doses only	Vaccinated three doses only	Vaccinated four doses	*p-value*
Number (%)		4610 (12.7)	470 (1.3)	17897 (49.5)	12369 (34.2)	824 (2.3)	-
Age, years Median (IQR)	33 (24,46)	32 (23,47)	30 (23,43)	29 (22,43)	38 (28,49)	38 (30,47)	<0.01
Age group, n (%)
18-29	14981 (41.4)	1995 (43.3)	234 (49.8)	8977 (50.2)	3595 (29.1)	180 (21.8)	<0.01
30-39	7712 (21.32)	936 (20.3)	89 (18.9)	3342 (18.7)	3086 (24.9)	259 (31.4)
40-49	6276 (17.3)	703 (15.2)	75 (15.9)	2617 (14.6)	2649 (21.4)	232 (28.2)
50-59	4125 (11.4)	530 (11.5)	36 (7.7)	1729 (9.7)	1697 (13.7)	133 (16.1)
60-69	2340 (6.5)	338 (7.3)	26 (5.5)	922 (5.1)	1038 (8.4)	16 (1.9)
≥70	736 (2.0)	108 (2.3)	10 (2.1)	310 (1.7)	304 (2.5)	4 (0.5)
Gender, n (%)
Male	16783 (46.4)	2236 (48.5)	243 (51.7)	8488 (47.4)	5434 (43.9)	382 (46.4)	<0.01
Female	19387 (53.6)	2374 (51.5)	227 (48.3)	9409 (52.6)	6935 (56.1)	442 (53.6)	<0.01
Median (IQR) time since last vaccination, days	85 (53,122)	-	102 (52,141)	110 (84,150)	53 (35,75)	40 (26,57)	-

Supplementary Table 1a. Vaccine Effectiveness Against SARS-CoV-2 Infection In Adults, during Delta predominance (1 Oct 2021- 31 Dec 2021)

	Crude OR	95% CI-lower	95% CI-upper	*p-value*	Crude VE	95% CI-upper	95% CI-lower	Adjusted OR	95% CI-lower	95% CI-upper	*p-value*	Adjusted VE	95% CI-upper	95% CI-lower
Age,years	1.00	0.99	1.00	0.11
Gender
Female	Ref
Male	1.12	1.02	1.22	<0.01
Calendar week of test	0.97	0.95	0.98	<0.01
Vaccination status¹
Unvaccinated	Ref							Ref
One dose only	0.90	0.80	1.03	0.14	10	20	-3	0.92	0.81	1.05	0.24	8	19	-5
Two doses only	0.39	0.35	0.43	<0.01	61	65	57	0.37	0.33	0.41	<0.01	63	67	59
Three doses only	0.03	0.01	0.07	<0.01	97	99	93	0.03	0.01	0.06	<0.01	97	99	94
Vaccination status by age (years)²
Unvaccinated	Ref							Ref
18-29
Two doses only	0.36	0.30	0.43	<0.01	64	70	57	0.35	0.29	0.44	<0.01	65	71	56
Three doses only	No cases observed
30-39
Two doses only	0.36	0.29	0.45	<0.01	64	71	55	0.36	0.29	0.44	<0.01	64	71	56
Three doses only	0.05	0.01	0.18	<0.01	95	99	82	0.04	0.01	0.16	<0.01	96	99	84
40-49
Two doses only	0.45	0.36	0.57	<0.01	55	64	43	0.44	0.35	0.56	<0.01	56	65	44
Three doses only	0.05	0.01	0.21	<0.01	95	99	79	0.04	0.01	0.19	<0.01	96	99	81
>=50
Two doses only	0.39	0.33	0.48	<0.01	61	67	52	0.38	0.31	0.46	<0.01	62	69	54
Three doses only	0.02	0.00	0.19	<0.01	98	100	81	0.02	0.00	0.16	<0.01	98	100	84
Third vaccine dose type¹
Unvaccinated	Ref							Ref
PFZ	No cases observed
AZ	0.04	0.01	0.10	<0.01	96	99	90	0.07	0.03	0.18	<0.01	93	97	82
Mod	No cases observed

AZ=ChAdOx1 (AstraZeneca), PFZ=BNT162b2 (Pfizer-BioNTech), Mod=Spikevax (Moderna), Ref=Reference

1 Adjusted for age, gender, and calendar time, 2 Adjusted for gender and calendar time

Supplementary Table 1b. Vaccine Effectiveness Against SARS-CoV-2 Infection In Adults, during Omicron predominance (1 Feb 2022-10 Apr 2022)

	Crude OR	95% CI-lower	95% CI-upper	*p-value*	Crude VE	95% CI-upper	95% CI-lower	Adjusted OR	95% CI-lower	95% CI-upper	*p-value*	Adjusted VE	95% CI-upper	95% CI-lower
Age,years	0.98	0.98	0.99	<0.01
Gender
Female	Ref
Male	0.98	0.94	1.02	0.38
Calendar week of test	1.24	1.23	1.25	<0.01
Vaccination status¹
Unvaccinated	Ref							Ref
Vaccinated One dose only	1.01	0.83	1.22	0.90	-1	17	-22	0.92	0.75	1.13	0.48	8	25	-13
Vaccinated two doses only	1.11	1.04	1.18	<0.01	-11	-4	-18	1.04	0.97	1.12	0.19	-4	3	-12
Vaccinated three doses only	0.77	0.72	0.82	<0.01	23	28	18	0.69	0.64	0.74	<0.01	31	36	26
Vaccinated four doses	0.36	0.30	0.44	<0.01	64	70	56	0.25	0.20	0.29	<0.01	75	80	71
Vaccination status by age (years) ²
Unvaccinated	Ref							Ref
18-29
Vaccinated three doses	0.86	0.77	0.96	<0.01	14	23	4	0.65	0.57	0.73	<0.01	35	43	27
Vaccinated four doses	0.54	0.39	0.76	<0.01	46	61	24	0.33	0.23	0.47	<0.01	67	77	53
30-39
Vaccinated three doses	0.67	0.58	0.78	<0.01	33	42	22	0.66	0.56	0.78	<0.01	34	44	22
Vaccinated four doses	0.33	0.24	0.47	<0.01	67	76	53	0.23	0.17	0.33	<0.01	77	83	67
40-49
Vaccinated three doses	0.78	0.66	0.93	<0.01	22	34	7	0.67	0.56	0.81	<0.01	33	44	19
Vaccinated four doses	0.31	0.21	0.46	<0.01	69	79	54	0.20	0.13	0.30	<0.01	80	87	70
>=50
Vaccinated three doses	0.87	0.75	1.01	0.08	13	25	-1	0.81	0.69	0.95	0.01	19	31	5
Vaccinated four doses	0.37	0.24	0.57	<0.01	63	76	43	0.28	0.18	0.44	<0.01	72	82	56
Third vaccine dose type³
Unvaccinated	Ref							Ref
PFZ	0.77	0.71	0.83	<0.01	23	29	17	0.69	0.56	0.85	<0.01	31	44	15
AZ	0.75	0.68	0.81	<0.01	25	32	19	0.74	0.60	0.92	<0.01	26	40	8
Mod	0.84	0.75	0.93	<0.01	16	25	7	0.69	0.55	0.87	<0.01	31	45	13
Fourth vaccine dose type³
Unvaccinated	Ref							Ref
PFZ	0.36	0.27	0.45	<0.01	64	73	55	0.29	0.21	0.40	<0.01	71	79	60
AZ	0.28	0.14	0.58	0.01	72	86	42	0.27	0.11	0.52	<0.01	73	89	48
Mod	0.39	0.29	0.50	<0.01	61	71	50	0.29	0.21	0.41	<0.01	71	79	59

AZ=ChAdOx1 (AstraZeneca), PFZ=BNT162b2 (Pfizer-BioNTech), Mod=Spikevax (Moderna), Ref=Reference

1 Adjusted for age, gender, and calendar time

2 Adjusted for gender and calendar time

3 Adjusted for age, gender, calendar time and preceding vaccine series type

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Effectiveness of heterologous 3^rd and 4^th dose COVID-19 vaccine schedules for SARS-CoV-2 infection during delta and omicron predominance in Thailand.

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﻿Effectiveness of heterologous 3rd and 4th dose COVID-19 vaccine schedules for SARS-CoV-2 infection during delta and omicron predominance in Thailand.

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Effectiveness of heterologous 3^rd and 4^th dose COVID-19 vaccine schedules for SARS-CoV-2 infection during delta and omicron predominance in Thailand.