1.
With reference to the media statement dated 9 February 2022 (link) by Pharmaniaga
Berhad regarding the lower effectiveness of heterologous boosting for Sinovac
primary vaccination recipients against Omicron, the Ministry of Health Malaysia wishes
to state that the prevailing facts and evidence are misrepresented.
Globally, there is emerging and consistent evidence that heterologous booster
vaccination results in more robust immune responses and is more effective than
homologous boosting for recipients of primary series of inactivated vaccines
(Sinovac).
A study in the Dominican Republic[1] highlighted that neutralization against the
Omicron variant was undetectable in participants who had received two doses of
Sinovac. A Pfizer booster (heterologous mRNA vaccine booster) resulted in a 1.4-
fold higher neutralization activity against Omicron when compared to only two doses
of mRNA vaccine. Despite this increase, the neutralizing antibody titres were still
lower for Omicron compared to ancestral and Delta variants. In this study, there was
no homologous booster (Sinovac) group of participants to allow comparison
between heterologous and homologous boosting regimen.
Two separate other studies compared heterologous against homologous booster
regiments for Sinovac primary series recipients. In a study done in Hong Kong
SAR[2], heterologous Pfizer booster following two doses of Sinovac improved
neutralizing antibody levels against Omicron variant at 3-5 weeks post-booster dose
but three doses of Sinovac failed to elicit neutralizing antibody responses to Omicron
in most recipients. In another study conducted in Brazil[3], heterologous boosting
(with AstraZeneca, Janssen and Pfizer ) resulted in more robust immune responses
than homologous boosting (with Sinovac booster), hence potentially stronger
protection. The study found that heterologous booster doses of AstraZeneca, Janssen
and Pfizer vaccines substantially increased the neutralizing capacity of serum samples
against both Delta and Omicron variants (at least 90% seropositive after booster),
compared to strikingly lower responses observed after a homologous Sinovac
booster with only 35% becoming seropositive against Omicron.
REVIEW OF EVIDENCE: HETEROLOGOUS AND HOMOLOGOUS
BOOSTING FOR SINOVAC PRIMARY SERIES RECIPIENTS
Institute for Clinical Research,
Ministry of Health, Malaysia
10 February 2022
ICR
MINISTRY OF HEALTH MALAYSIA
Research that matters to patients

2.
In an interim statement on booster doses[4], the WHO remarked that both
homologous and heterologous booster regimens are immunologically effective.
However, it is not possible to predict with high confidence the performance of
vaccines based on immune responses alone, as no correlate of protection has yet
been defined. Further evidence from real-world settings will therefore be useful. A
preprint from a study conducted in Chile[5], based on real-world data (a national
cohort data of 11.2 million people), observed an adjusted vaccine effectiveness
against symptomatic COVID-19 of 78.8% for three doses of Sinovac, 96.5% for Pfizer
booster (following two doses of Sinovac) and 93.2% for AstraZeneca booster
(following two doses of Sinovac). The observed effectiveness against hospitalization,
ICU admission and COVID-19 related deaths were also higher for heterologous
boosters (Pfizer, AstraZeneca) than homologous booster (Sinovac).
In Malaysia, The Real-World Effectiveness of COVID-19 Vaccine under the Malaysian
National COVID-19 Immunisation Program (RECoVaM, NMRR 21-1660-60697)
study used data from 21 November 2021 until 7 January 2022 to compare the
COVID-19 infection rates among recipients of booster doses and those who had
only completed primary vaccination (at least 14 days after receiving booster or
primary doses). The analysis is based on real-world data, which included 13 million
people who had received Pfizer and Sinovac primary vaccination series.
After accounting for confounders, those who have just received booster doses were
at least 90% less likely to be infected with COVID-19 than those with only two
doses. Among Sinovac recipients, a heterologous booster (Sinovac primary
vaccination, followed by a Pfizer booster) offered greater protection against infection
than a homologous booster dose (three doses of Sinovac).

3.
The WHO advises that where countries are considering heterologous schedules,
depending on product availability, mRNA or viral vector vaccines can be considered
as third dose in those who received inactivated vaccines for initial doses[6]. In line
with emerging evidence and the ongoing Omicron wave, the Ministry of Health
Malaysia continues to recommend Pfizer or AstraZeneca as the preferred booster for
Sinovac vaccine recipients.
References:
1. Pérez-Then E, Lucas C, Monteiro VS, et al. Neutralizing antibodies against the SARS-CoV-2 Delta
and Omicron variants following heterologous CoronaVac plus BNT162b2 booster vaccination. Nat
Med (2022). https://doi.org/10.1038/s41591-022-01705-6
2. Cheng SMS, Mok CKP, Leung YWY, et al. Neutralizing antibodies against the SARS-CoV-2
Omicron variant following homologous and heterologous CoronaVac or BNT162b2 vaccination. Nat
Med (2022). https://doi.org/10.1038/s41591-022-01704-7
3. Clemens SAC, Weckx L, Clemens R, et al. Heterologous versus homologous COVID-19 booster
vaccination in previous recipients of two doses of CoronaVac COVID-19 vaccine in Brazil (RHH-
001): a phase 4, non-inferiority, single blind, randomised study. The Lancet. 2022.
4. World Health Organization. Interim statement on booster doses for COVID-19 vaccination.
Updated 22 Dec 2021. Available from: https://www.who.int/news/item/22-12-2021-interim-
statement-on-booster-doses-for-covid-19-vaccination---update-22-december-2021.
5. Jara A, Undurraga EA, Zubizarreta JR, et al. Effectiveness of Homologous and Heterologous Booster
Shots for an Inactivated SARS-CoV-2 Vaccine: A Large-Scale Observational Study. Available at
SSRN: https://ssrn.com/abstract=4005130 or http://dx.doi.org/10.2139/ssrn.4005130
6. World Health Organization. Interim recommendations for heterologous COVID-19 vaccine
schedules. Updated 16 Dec 2022. Available from: https://www.who.int/publications/i/item/WHO-
2019-nCoV-vaccines-SAGE-recommendation-heterologous-schedules.