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Recommendations For Heterologous COVID-19 Vaccine Schedules By WHO

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written by Shield Connect

The Strategic Advisory Group of Experts on Immunization (SAGE) provided inputs to generate the interim heterologous COVID-19 vaccine recommendations.

The Strategic Advisory Group of Experts on Immunization (SAGE) provided inputs to generate the interim heterologous COVID-19 vaccine recommendations. As of December 7, 2021, the recommendations apply to all COVID-19 vaccines that have acquired a WHO Emergency Use Listing (EUL) (Ad26.COV2.S, BBV152, BNT162b2, ChAdOx1-S [recombinant], mRNA-1273, Sinopharm-BIBP, and Sinovac-CoronaVac).1

Rationale for heterologous vaccine schedules

The risks and benefits of COVID-19 vaccinations have primarily been examined using the same vaccine products throughout the dosing series, whether delivered as a primary series or as booster doses. Owing to this, homologous vaccination is now considered as a common practice. Although lack of availability of the same vaccine product in a location is a common rationale for contemplating heterologous COVID-19 vaccine regimens. Further reduced reactogenicity, increased immunogenicity, and improved vaccine effectiveness are the other reasons to adopt heterologous vaccine regimens.

Below are the few points to consider for heterologous use of COVID vaccine

  1. Vaccine effectiveness

Several observational studies employing WHO EUL COVID-19 vaccines have now reported on vaccination efficacy (VE) following heterologous primary or boosting schedules. The main regimens of most of the studies includes ChAdOx1-S and an mRNA vaccination. Short-term efficacy against infection or symptomatic disease after heterologous ChAdOx1-S/mRNA rages from 61 to 91% which is slightly better than, homologous ChAdOx1-S (43–89%), reaching levels like those seen after two doses of mRNA vaccine (69–90 %). (3-5).

Till date, two studies have reported the efficacy after heterologous boosting. One study in the United Kingdom demonstrates, heterologous boosting with BNT162b2 after a primary series of ChAdOx1-S had a VE against symptomatic disease of 93% (95 % [CI]: 92–94 percent) compared to unvaccinated individuals, and a relative VE of 87 % (95 % [CI]: 85–89 percent) compared to individuals who had received a primary series of ChAdOx1-S at least 140 days prior to onset but no booster dose. The VE and relative VE after a homologous booster dose of BNT162b2 after a primary series of BNT162b2 were similar (94 %) [95 % CI: 93–95 percent] and 84 % [95 % CI: 83–86 percent], respectively.2

In another study, heterologous boosting with either ChAdOx1-S or BNT162b2 among Sinovac-CoronoVac primed individuals was linked to higher VE than homologous boosting against infection (90% for ChAdOx1-S; 93% for BNT162b2; and 68% for Sinovac-CoronoVac); symptomatic disease (93%, 95% and 71% respectively); hospitalization (96%, 89% and 75% percent) and ICU admission (98%, 90%, and 79% respectively).3

  1. Immunogenicity 4

A wide range of vaccine combinations and dose regimens, data on the immunogenicity of heterologous schedules is presently available. Although lack of established data on schedule intervals and long-term consequences and based on some observational evidences current strategy should be used with caution.

Nonetheless, a few persistent trends emerge from the current research:

Inactivated vaccines:

When inactivated vaccines are given before or after vectored vaccines (post vaccination heterologous/homologous binding antibody [Ig] ratios of 3–9 across 6 studies) or mRNA vaccines (Ig ratios of 11–33 across 4 studies), heterologous schedules consistently show improved immunogenicity compared to homologous inactivated-only schedules. Majority of the studies exhibit that the inactivated vaccination was given first, followed by the vectored or mRNA vaccine. Antibody levels were higher in the Sinovac CoronaVac/ChAdOx1-S (4-week interval) group than in the ChAdOx1-S/Sinovac-CoronaVac (10-week interval) group in one cohort study, with both heterologous groups having higher antibody concentrations than homologous Sinovac-CoronaVac patients (4-week interval).

Vectored vaccines:

When vectored vaccines are administered before or after mRNA vaccines (Ig ratios of 4–14 across 15 studies), but not inactivated vaccines (Ig ratios of 0.4–3 across 6 studies, of which 5 studies reported ratios of 1), heterologous schedules consistently show enhanced immunogenicity (Ig ratios of 4–14 across 15 studies).The majority of mRNA vaccination trials compared the effects of a vectored vaccine followed by an mRNA vaccine. One clinical trial found that ChAdOx1-S/BNT162b2 recipients had higher antibody concentrations than heterologous COVID-19 vaccine schedules -3- BNT162b2/ChAdOx1-S recipients, with both heterologous groups having higher antibody concentrations than homologous ChAdOx1-S recipients (with 4-week intervals).

mRNA vaccines:

When mRNA vaccines are administered before or after vectored vaccines (Ig ratio of 0.4–8 across 16 studies) or inactivated vaccines, heterologous schedules have demonstrated no convincing evidence of improved immunogenicity when compared to homologous mRNA-only schedules (Ig ratio of 0.5 in 1 study). The majority of studies (10 of 16) using vectored vaccines found post-vaccination Ig ratios in the range of 0.7 to 1.4, showing that the heterologous and homologous regimens are roughly equivalent. These patterns are comparable when neutralising antibody concentrations are used as an endpoint in observational research and clinical trials (in which parameters such as dose interval could be better controlled).

  1. Safety 5,6

Most of the heterologous product combinations have limited safety evidence. When heterologous schedules have been compared to homologous schedules, they have often demonstrated transiently increased reactogenicity. When ChAdOx1-S or Ad26.COV2.S are administered after mRNA vaccines, or when BNT162b2 or mRNA-1273 are administered after vectored vaccines, some studies have reported a higher frequency of local and systemic side effects (such as headache and fatigue) when compared to homologous vaccination schedules (9, 15-17). For both homologous and heterologous regimens, the majority of adverse effects are mild or moderate, and they usually go away within 1–3 days of vaccination. With the vaccines BNT162b2 and mRNA-1273, a very rare signal of myocarditis/pericarditis has been recorded. Myocarditis and these vaccines appear to have a causal relationship, according to current research.

Recommendations by WHO7

Homologous schedules are considered standard practice based on substantial safety, immunogenicity, and efficacy data available for each WHO EUL COVID-19 vaccine. However, WHO supports a flexible approach to homologous versus heterologous vaccination schedules, and heterologous vaccination should only be implemented with careful considerations. For countries considering heterologous schedules, WHO makes the following recommendations

  • Countries implementing WHO EUL inactivated vaccines for initial doses may consider vectored or other mRNA vaccine for the subsequent doses.
  • Countries implementing WHO EUL vectored vaccines for the initial doses may consider WHO EUL mRNA vaccines for subsequent doses.
  • Countries implementing WHO EUL mRNA vaccines for the first dose may consider using WHO EUL vectored vaccines for subsequent doses.


  1. Meeting of the Strategic Advisory Group of Experts on Immunization (SAGE) – 7 December 2021 (http://www.who.int/news-room/events/detail/2021/12/07/default-calendar/extraordinary-meeting-of-the-strategicadvisory-group-of-experts-on-mmunization-(sage)-7-december-2021, accessed 15 December 2021.
  2. Araos R, Jara A. Covid-19 vaccine effectiveness assessment in Chile – 25 October 2021 (https://cdn.who.int/media/docs/default-source/blue-print/chile_rafael-araos_who-vr call_25oct2021.pdf?sfvrsn=7a7ca72a_7, accessed 29 November 2021).
  3. Skowronski DM, Setayeshgar S, Febriani Y, Ouakki M, Zou M, Talbot D et al. Two-dose SARS-CoV-2 vaccine effectiveness with mixed schedules and extended dosing intervals: test-negative design studies from British Columbia and Quebec, Canada. medRxiv. doi: 10.1101/2021.10.26.21265397.
  4. Wanlapakorn N, Suntronwong N, Phowatthanasathian H, Yorsaeng R, Vichaiwattana P, Thongmee T et al. Safety and immunogenicity of heterologous and homologous inactivated and adenoviral-vectored COVID-19 vaccines in healthy adults. medRxiv. doi: 10.1101/2021.11.04.21265908.
  5. Hillus D, Schwarz T, Tober-Lau P, Vanshylla K, Hastor H, Thibeault C et al. Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study. Lancet Respir Med. 2021;9:1255-65. doi: 10.1016/S2213-2600(21)00357-X.
  6. Benning L, Tollner M, Hidmark A, Schaier M, Nusshag C, Kalble F et al. Heterologous ChAdOx1 nCoV-19/BNT162b2 prime-boost vaccination induces strong humoral responses among health care workers. Vaccines. 2021;9:857. doi: 10.3390/vaccines9080857.
  7. https://apps.who.int/iris/bitstream/handle/10665/350635/WHO-2019-nCoV-vaccines-SAGE-recommendation-heterologous-schedules-2021.1-eng.pdf?sequence=1.
Dr Sudhanshu Seekhar Nath Dr Sudhanshu Seekhar Nath M.S. (O&G)
Assistant Professor, VIMSAR, Burla, Odisha.


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